UK Patent Application ,»,GB ,,,,2405793 ™A
(43) Date of A Publication 18.03.2005
(21)
Application No:
0321384.0
(51)
INT CL 7 :
A61K 31/519 . A61P 37/06 39/00
(22)
Date of Filing:
12.09.2003
(52)
UK CL (Edition X ):
A5B BHA B180 B42Y B423 B48Y B480 B50Y B502 B504
(71)
Applicants):
B51Y B511 B513 B54Y B541 B542 B55Y B552 B553
4 AZA Bioscience nv
B56Y B565 B566 B57Y B576 B58Y B586 B60Y B606
(Incorporated in Belgium)
B65Y B650 B657 B67Y B670
Kapuctjnenvoer 33, B-3000 Leuven,
Belgium
(56)
Documents Cited:
WO 2000/039129 A1 DE 019944767 A
(72)
Inventor(s):
JP 060192100 A JP 2003238409 A
Piet Herdewijn
US 5902810 A
Mark Waer
Steven Cesar Alfons De Jonghe
(58)
Field of Search:
Un Yuan
INT CL 7 A61K,A61P
Sefrioui El Hassane
Other WPI. EPODOC, JAPIO, CAS-ONUNE
(74)
Agent and/or Address for Service:
Bird Goen & Co
155 Regents Park Road LONDON,
NW1 8BB, United Kingdom
(54) Abstract Title: Pteridine derivatives for treating TNF-alpha related disorders
(57) This invention relates to the use of a group of pteridine derivatives, their pharmaceutical^ acceptable
salts, N-oxides, solvates, dihydro- and tetrahydroderivatives and enantiomers, for the manufacture of a
medicament for the prevention or treatment of TNF-cc related disorders. The pterin preferably has an
amino, or acetamino in the 2 position; hydroxy, an alkoxy, dialkylamino, dibenzylamino, a N containing
heterocycle or an adamantylamino group in the 4 position; a hydrogen, styryl, or optionally substituted
phenyl in the 6 position; and hydrogen, methyl or methoxy in the 7-position. The condition K may be
septic or endotoxic shock, toxic effects of radiotherapy, TNF-ct or chemotherapeutic agents, or cachexia.
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Original Printed on Recycled Paper
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Figure 1
CI
H J
R 2 ^ S N NH2
XR,
nV no
R 2 ^N NH 2
XR,
I! X
R 7 '' NH2
XR t
XR1
N'VS
6
XR,
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R 2 ^ N N
XR,
Figure 2
R^N^NM, R^N^NH, R 2 ^N^NH 2
9 10 11
o n 3
HON J
« 13
?1
X
k. JU
R 2 N N
Figure 4
J J
NH 2
4
H 3 C
N ^
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NH3
O
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R 2 V N
NH 2
I
IT •*
R 2 N X N
O
J II
R/" VV^R,
NH 2
R 2 N N
NH 2
R^N^NHj
NH2
R 2 '^n' NHj
X
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R 2 'W
V
X
R 2 A<V^R«
Figure 5
o
X
H
► HN
O
7l JC
H
CI
C | /V N" NH 2
1
X
X " N
i 1
N V NH2
X' *
?1
X
nV NOj
0 I
X
.JL
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N N - Rj
2405793
1
PTERIDINE DERIVATIVES FOR THE TREATMENT OF SEPTIC SHOCK
AND TNF-a-RELATED DISEASES.
FIELD OF THE INVFNTION
5 The present invention relates to a novel medical indication of pteridine
derivatives for the treatment of side effects of various chemotherapeutic drugs
and/or of irradiation in cancer therapy. The present invention also relates to
the use of polysubstituted pteridines for the prevention and/or the treatment of
pathologic and inflammatory conditions such as septic shock, as well as toxic
10 side effects, disorders and diseases related to or resulting from the exposure
of patients to abnormally high levels of tumor necrosis factor-alpha
(hereinafter referred as TNF-a) in general, and particularly following the
administration of TNF-a in cancer treatment in humans. This invention also
relates to the use of polysubstituted pteridines for the prevention and/or the
15 treatment of radiotherapy-induced or chemotherapy-induced disorders such
as mucositis, secondary myelodysplastic syndromes and radiation-induced
graft-versus-host disease, and for the prevention and/or the treatment of
injuries in cancer patients such as, but not limited to, apoptosis, radiation
necrosis and nephrotoxicity following the administration of certain
20 chemotherapeutic drugs such as cisplatin in cancer treatment Additionally the
invention relates to the treatment of cachexia
BACKGROUND OF THE INVENTION
Several 2,4-diaminopteridine derivatives, including methotrexate are
25 known in the art (for instance, see U.S. Patent No. 2,512,572) as being useful as
antineoplastic agents
Nevertheless, there still is a need in the art for specific and highly
therapeutically active compounds, such as, but not limited to, drugs for
preventing or treating cell proliferative disorders, including cancer. In
30 particular, there is a need in the art to provide anti-cancer drugs which are
active in a minor dose or in minimizing the side effects of other known and
efficient anti-cancer drugs or radio-active treatments.
10
Septic shock is a major cause of death in intensive care units (about
150,000 estimated deaths annually in the United States of America, despite
treatment with intravenous antibiotics and supportive care) for which very little
effective treatment is available at present. Patients with severe sepsis often
experience failures of various systems in the body, including the circulatory
system, as well as kidney failure, bleeding and clotting. Upopolysaccharide
(hereinafter referred as LPS) is the primary mediator of Gramm-negative
sepsis, the most common form of sepsis, by inducing the production of a
whole array of macrophage-derived cytokines (such as TNF-a; interleukins
such as IL-1, IL-6, IL-12; interferon-gamma (hereinafter referred IFN-y), etc.).
These cytokines may induce other cells (e.g. T cells, NK cells) to make
cytokines as well (e.g. IFN^y). In addition, other macrophage products (e.g.
nitric oxide, hereinafter referred as NO) may also play a role in the
pathogenesis of toxic shock. These substances (e.g. NO) may be induced
15 directly due to microbial interactions or indirectly through the action of
proinflammatory cytokines. LPS binds to a serum protein known as LPB and
the LPS-LPB complex thus formed is recognized by the CD14 toll-like receptor
4 (hereinafter referred as Tlr 4) complex on mononuclear phagocytes. Tlr4 is a
signal transducing unit, the activation of which results in the release of
mediators such as TNF-a, IL-1a, IL-ip and IL-6. These cytokines are
important for the pathogenesis of shock. Their administration produces the
clinical symptoms of septic shock and their blockade partially protects against
LPS-induced lethal shock.
Current therapeutic strategies for the treatment of septic shock are
25 directed against LPS (e.g. antibodies against LPS or LBP-34-23) or against
the cytokines induced by LPS (e.g. TNF antibodies) or against the receptor for
LPS (e.a. CD14) Unfortunately the initial clinical data of these approaches are
very disappointing and illustrate the redundancy of receptors and mediators
involved in the pathogenesis of toxic shock. For instance flagellin seems to be
30 another foxin that plays a role in Gramm-negative Salmonella shock syndrome
and that cannot be prevented or treated by therapeutic strategies directed
specifically at LPS.
20
3
Clinical trials in humans with TNF-a blocking antibodies (such as the IL-
1 receptor antagonist or PAF receptor antagonists) have been unsuccessful
yet, as have been approaches to down regulate inflammation (e.g. using
prednisolone) or to block endotoxins. These products must be administered
5 very early after the onset of the disease, which is in most cases not possible.
The only drug currently approved by health authorities for the treatment
of adult patients with the most serious forms of sepsis, including septic shock,
is a genetically engineered version of a naturally occurring human protein,
Activated Protein C, known as Xigris® or drotecogin-alpha which shows only
10 moderate efficacy. Furthermore, because Activated Protein C interferes with
blood dotting, the most serious side effect associated with Xigris® is bleeding,
including bleeding that causes stroke Thus Xigris® is contra-indicated for
patients who have active internal bleeding, or who are more likely to bleed
because of certain medical conditions including recent strokes, recent head or
15 spinal surgery or severe head trauma. Beacause treatment with Xigris® comes
with potentially serious risks, the benefits and risks of treatment with Xigris®
must be carefully weighed for each individual patient.
Therefore there is a strong need in the art for new medications, either
alone or in combination with the currently suggested treatments, for treating
20 the most serious forms of life-threatening illnesses caused by severe infection,
such as septic shock.
TNF-a is generally considered to be the key mediator in the mammalian
response to bacterial infection. It is a strong pro-inflammatory agent that will
affect the function of almost any organ system, either directly or by inducing
25 the formation of other cytokines like IL-1 or prostaglandines TNF-a is also a
potent anti-tumor agent. If administered in small quantities to humans, it
causes fever, headache, anorexia, myalgia, hypotension, capillary leak
syndrome, increased rates of lipolysis and skeletal muscle protein degradation
(including cachexia). Its use in cancer treatment is therefore very much limited
30 by its severe side effects.
TNF-a, a pleiotropic cytokine produced mainly by activated
macrophages, exerts an in vitro cytotoxic action against transformed cells and
in vivo anti-tumor activities in animal models. However, despite the fact that
TNF-a is used in cancer patients especially to treat melanoma and sarcoma,
the major problem hampering its use is toxicity. Indeed, TNF-a induces shock-
like symptoms such as bowel swelling and damage, liver cell necrosis,
enhanced release of inflammatory cytokines such as IL-1 or IL-6. and
5 hypotension probably due to the release of inducers of vessels dilatation such
nitric oxide and other proinflammatory cytokines. Cardiovascular toxicity is
usually dose-limiting. Hypotension can be severe with systolic Wood pressure
below 60 mm Hg. Respiratory compromise is common after treatment with
TNF-a and may require mechanical ventilation. Upper as well as lower
10 digestive tract symptoms are also common in this type of treatment. Nausea
and vomiting can be distressing and in some cases dose-limiting ; Watery
diarrhea is frequently observed. Neurological sequelae of treatment with TNF-
a can also occur.
Hence, compounds that inhibit the toxic effects of TNF-a but that do not
1 5 inhibit TNF-a anti-tumor effect are highly desirable for the treatment of cancer
patients. Presently, several clinical trials involving TNF-a are being developed
for the cancer of organs such as liver, lung, kidney and pancreas, which are
based on a procedure including the steps of organ isolation, injection of TNF-
a into the isolated organ, and reperfusion of the treated organ. However, even
20 for isolated organ perfusion, some TNF-a usually escapes to the general
blood circulation and leads to the mortality of about 10% of the patients thus
treated. Many patients treated by this procedure also require intensive care
unit rescue to cope with the toxic side-effects of such TNF-a treatment.
Combined treatment of TNF-a with alkylating drugs in an isolated organ
25 perfusion model has received considerable attention. TNF-a is currently
successfully used in isolated limb perfusion of human cancer patients and, in
combination with melphalan and interferon-gamma, against melanoma,
sarcomas and carcinomas.
The gastrointestinal mucosa is very sensitive to chemotherapeutic
30 drugs Mucositis caused by chemotherapy usually begins rapidly after
initiation of the treatment with inflammation and ulceration of the
gastrointestinal tract and leading to diarrhea. Severe, potentially life-
threatening, diarrhea may require interruption of the chemotheraputic
treatment and subsequent dose reduction of the therapeutic agent. The oral
cavity is often the place of severe side effects from cancer therapy that
adversely affects the quality of life of the patient and its ability to tolerate the
5 therapy. These side effects can be caused by radiotherapy as well as
chemotherapy. A relationship between both serum and mucosal levels of
TNF-o and IL-1 correlates with nonhematologic toxicities, including mucositis.
Radiation injuries occurring e.g. after a single high-dose irradiation
include apoptosis as well as radiation necrosis. Even normal tissues protected
by shielding during irradiation may be considerably damaged. It was found in
experimental animal models that the radiation injuries after a single high-dose
irradiation typically used for the treatment of various malignant tumors consist
of radiation necrosis and apoptosis, which were correlated with the expression
of TNF-a and TGF-pi .
Irradiation may induce graft-versus-host disease (hereinafter referred
as GVHD) in cancer patients. This disease may occur especially in patients
receiving allogeneic* bone marrow transplantation as a treatment for cancers
such as leukemia or lymphoma and can lead to the death of about 25% of the
relevant patients. Before bone marrow transplantation, leukaemia patients for
example receive either total body or total lymphoid irradiation to suppress their
immune system. However, such irradiation induces not only necrosis but also
the release of proinflammatory cytokines mainly TNF-a, IL-1 and IL-6 which in
turn induce direct host tissues inflammation and activation of donor cells
against host antigens leading to GVHD.
Cisplatin is an effective chemotherapeutic agent used in the treatment
of a wide variety of both pediatric and adult malignancies, including testicular,
germ cell, head and neck (cervical), bladder and lung cancer. Dose-
dependent and cumulative nephrotoxicity is the major side effect of cisplatin,
sometimes requiring a reduction in dose or discontinuation of the treatment.
Other side effects of cisplatin include kidney damage, loss of fertility, harmful
effect on a developing baby, temporary drop in bone marrow function causing
drop in white blood cell count, anaemia, drop in platelets causing bleeding,
loss of appetite, numbness or tingling in limbs, loss of taste, allergic reactions,
and hearing disorders (difficulty in hearing some high-pitched sounds,
experiencing ringing in the ears). Blurred vision may also be a side effect with
high doses of cisplatin. It was shown that TNF-a is a key element in a network
5 of proinflammatory chemokines and cytokines activated in the kidney by
cisplatin. Blockade of TNF-a action would prevent the activation of this
cytokine network and would provide protection against cisplatin nephrotoxicity.
Hence, compounds that inhibit the toxic effects of cisplatin but that do not
inhibit cisplatin anti-tumor effects are highly desirable for the treatment of
10 cancer patients.
A surplus of TNF-a also causes a dramatic change of endothelial cells.
In particular, TNF-a is an important mediator of skeletal muscle degeneration
associated with cachexia, a debilitating syndrome characterized by extreme
weight loss and whole-body wasting. Cachexia is usually a secondary
15 condition whereby there is excessive tissue catabolism in combination with
deficient anabolism. It is frequently seen in patients afflicted with chronic
diseases such as cancer, cardiopulmonary diseases, aging, malabsortive
disorders, excessive physical stress, easting disorders and acquired
immmuno-deficiency syndrome (AIDS). Some authors consider that the
20 elevated TNF-a values found in at least 50% of cancer patients in the active
stage of the disease can result in cachexia. TNF-a levels in clinically healthy
adults, as well as in adult cancer patients, are well documented, for instance
by Nenova et al in Archives of Hellenic Medicine (2000) 17:619-621. Serum
TNF-a concentrations in healthy children as well as in children with
25 malignancies are documented for instance by Saarinen et al. in Cancer
Research (1990) 50:592-595. A very significant proportion of cancer
mortalities result from cachexia rather than from tumor burden. Chronic
wasting disease (cachexia) may result when excessive cellular damage
results in the release of substances (TNF-a, collagenase, hyaluronidase) that
30 further catabolize the so-called healthy tissue resulting in an inability to
assimilate nutrients required for anabolic restructuring of associated tissue.
Infants infected with human immunodeficiency virus type 1 (HIV-1)
show growth retardation and severe weight loss that can lead to death. The
7
overproduction of certain cytokines has been implicated as a possible cause
for this. For instance, according to Rautonen et al. in AIDS (1991) 5:1319-
1325, serum IL-6 concentrations are elevated and associated with elevated
TNF-o concentrations in children with HIV infection Swapan et al. in Journal
5 of Virology (2002) 76. 1 1 71 0-1 1 71 4 have shown that reduction of TNF-a levels
by either anti-TNF-a antibodies or human chorionic gonadotropin inhibits the
expression of HIV-1 proteins and prevents cachexia and death.
Very few drugs have been suggest at present for the treatment of
cachexia. Some high-dose progestins like megestrol acetate, an agent used
10 for the treatment of metastatic breast cancer, and medroxyprogesterone
acetate were shown in randomized clinical trials to provide a statistically
significant advantage as regards improved appetite and body weight gain
Hence, compounds that stimulate appetite and body weight gain without
inhibiting the anti-tumor effect or anti-viral effect of co-administered drugs are
IS highly desirable for the treatment of cachexia. More specifically, there is a
need in the art for treating cachexia by the administration of compounds that
reduce TNF-a levels in the serum of humans.
TNF-a is also suspected to play a role, through a possible dual action in
the hematopoietic environment, in the development of hematologic
20 malignancies such as idiopathic myelodysplastic syndromes occurring most
often in elderly people but also occasionally in children, these syndromes
being currently regarded as the early phase of acute leukemia.
There is a strong need in the art to improve, or to provide alternatives
to, the existing prophylactic or therapeutic solutions to all the aforesaid
25 diseases. Meeting this need in the art constitutes the main goal of the present
invention.
30
SUMMARY OF THE INVENTION
The present invention relates to the unexpected finding that a class of
pteridine derivatives having the general formula (I):
wherein X represents an oxygen atom or a group with the formula S(0)m
wherein m is an integer from 0 to 2, or a group with the formula NZ and wherein:
- Ri is a group selected from the group consisting of C1-7 alkyl, C2-7
alkenyl, C 2 . 7 alkynyl, C^o cycloalkyl, C^o cycloalkenyl, aryl, alkylaryl,
arylalkyl, heterocyclic, heterocyclic-substituted alkyl and alkyl-
substituted heterocyclic, each of said groups being optionally
substituted with one or more substituents selected from the group
consisting of halogen, C1-4 alkyl, Cm alkoxy, C 2 -? alkenyl, C 2 . 7 alkynyl,
halo Ci^j alkyl, C3-10 cycloalkoxy, aryloxy, arylalkyioxy, oxyheterocydic,
heterocyclic-substituted alkyloxy, thio C1.7 alkyl, thio C^o cycloalkyl,
thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio,
formyl, hydroxyl, suHhydryl, nitro, hydroxylamino, mercaptoamino,
cyano, carboxylic aad or esters or thioesters or amides or thioamides
or halides or anhydrides thereof, thiocarboxylic acid or esters or
thioesters or amides or thioamides or halides or anhydrides thereof,
carbamoyl, thiocarbamoyl, ureido, thio-ureido, amino, cydoalkylamino,
alkenylamino, cycloalkenylamino, alkynylammo, arylamino, arylalkyl-
amino, hydroxylalkylamino, mercaptoalkylamino, heterocyclic amino,
hydrazino, alkylhydraano and phenylhydrazino; or Ri is a carboxyalkyl,
carboxyaryl, thiocarboxyaryl or thiocarboxyalkyl group;
- Z is a group independently defined as Ri or Z is hydrogen or the group
NZ together with Rt is either hydroxylamino or an optionally substituted
heterocyclic group containing at least one nitrogen atom;
- R 2 is selected from the group consisting of amino; acyiamino;
thioacylamino, carbamoyl; thiocarbamoyl, ureido; thioureido, sulfon-
amide; hydroxylamino; alkoxyamino; thioalkylamino; mercaptoamino,
hydrazino; alkylhydrazino; phenylhydrazino; optionally substituted
heterocyclic radicals; Ci_ 7 alkylamino; arylamino; arylalkylamino;
cydoalkylamino; alkenylamino; cydoalkenylamino; heterocydic amino;
hydroxyalkylamino; mercaptoalkylamino; C1.7 alkoxy; C3-10 cycloalkoxy;
thio C1.7 alkyl; arylsulfoxide; arylsulfone; heterocyclic sulfoxide;
heterocyclic sulfone; thio C3-10 cycloalkyl; aryloxy; arylthio; arylalkyloxy;
arylalkylthio; oxyheterocyclic and thioheterocyclic radicals,
- R4 is an atom or a group selected from the group consisting of
hydrogen; halogen; C1.7 alkyl; C 2 - 7 alkenyl; C 2 - 7 alkynyl; halo C1-7 alkyl;
carboxy C,. 7 alkyl; acetoxy C1-7 alkyl; carboxyaryl; C,. 7 alkoxy; C3.10
cycloalkoxy; aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic-
substituted alkyloxy; thio C1.7 alkyl; thio C3-10 cycloalkyl; thioaryl;
thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; amino;
hydroxylamino; mercaptoamino, acylamino; thioacylamino; alkoxy-
amino; thioalkylamino; acetal; thioacetal; carboxylic acid; carboxylic
acid esters, thioesters, halides, anhydrides, amides and thioamides;
thiocarboxylic aad; thiocarboxylic acid esters, thioesters, halides,
anhydrides, amides and thioamides; hydroxyl, sulfhydryl; nitro; cyano;
carbamoyl; thiocarbamoyl, ureido; thio-ureido; alkylamino;
cycloalkylamino; alkenylamino; cycloalkenylamino; alkynylamino;
arylamino; arylalkylamino; hydroxyalkylamino; mercaptoalkylamino;
heterocyclic amino; heterocyclic-substituted alkylamino; oximino;
alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino; cysteinyl
acid, esters, thioesters, halides, anhydrides, amides and thioamides
thereof; aryl groups optionally substituted with one or more substituents
selected from the group consisting of halogen, C1.7 alkyl, C1.7 alkoxy,
C2-7 alkenyl, C2-7 alkynyl, halo C1.7 alkyl, nitro, hydroxyl, sulfhydryl,
amino, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyhetero-cyclic,
heterocyclic-substituted alkyloxy, thio C1.7 alkyl, thio C3-10 cycloalkyl,
thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio,
formyl, carbamoyl, thiocarbamoyl, ureido, thio-ureido, sulfonamido,
hydroxylamino, alkoxyamino, mercaptoamino, thioalkylamino, acyl-
amino, thioacylamino, cyano, carboxylic acid or esters or thioesters or
halides or anhydrides or amides thereof, thiocarboxylic acid or esters or
thioesters or halides or anhydrides or amides thereof, alkylamino,
cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino,
10
arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino,
heterocyclic amino, hydrazino, alkyl-hydrazino and phenylhydrazino;
optionally substituted heterocyclic radicals; aromatic or heterocyclic
substituents substituted with an aliphatic spacer between the pteridine
ring and the aromatic or heterocyclic substituent, whereby said aliphatic
spacer is a branched or straight, saturated or unsaturated aliphatic
chain of 1 to 4 carbon atoms which may contain one or more functions,
atoms or radicals selected from the group consisting of carbonyl (oxo),
thiocarbonyl, alcohol (hydroxyl), thiol, ether, thio-ether, acetal, thio-
acetal, amino, imino, oximino, alkyloximino, amino-acid, cyano,
acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-
ureido, carboxylic acid or ester or thioester or halide or anhydride or
amide, thiocarboxylic acid or ester or thioester or halide or anhydride or
amide, nitro, thio Ci_ 7 alkyl, thio C3-10 cycloalkyl, hydroxylamino,
mercaptoamino, alkylamino, cycloalkylamino, alkenylamino, cydo-
alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkyl-
amino, mercaptoalkylamino, heterocyclic amino, hydrazino,
alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl, sulfonamido and
halogen; branched or straight, saturated or unsaturated aliphatic chains
of 1 to 7 carbon atoms optionally containing one or more functions
selected from the group consisting of carbonyl (oxo), thiocarbonyl,
alcohol (hydroxyl), thiol, ether, thioether, acetal, thio-acetal, amino,
imino, oximino, alkyloximino, amino-acid, cyano, acylamino;
thioacylamino; carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic
acid ester or halide or anhydride or amide, thiocarboxylic acid or ester
or thioester or halide or anhydride or amide, nitro, thio C1.7 alkyl, thio
C3-10 cycloalkyl, hydroxylamino, mercaptoamino, alkylamino, cyclo-
alkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino,
arylalkylamino, hydroxyalkylamino, mercapto-alkylamino, heterocyclic
amino, hydrazino, alkylhydrazino, phenyl-hydrazino, sulfonyl, sulfinyl,
sulfonamido and halogen; and
11
- F*3 is an atom or a group defined as or R3 together with R4 forms a
homocyclic or heterocyclic radical such as, but not limited to, indolyl,
dihydroxypyrimidyl or tetra-methylene,
as well as pharmaceutical^ acceptable addition salts, stereoisomers, mono-
5 or di-A/-oxides, solvates and/or dihydro- or tetrahydropteridine derivatives
thereof, are useful for the manufacture of a medicament for the prevention or
treatment of a TNF-a-related disorder in a mammal, the said disorder being
selected from the group consisting of:
- septic or endotoxic shock,
1 0 - TNF-a- mediated diseases,
- pathologies and conditions associated with and/or induced by abnormal
levels of TNF-a occurring in a systemic, localized or particular tissue type
or location in the body of the mammal,
- toxic effects of TNF-a and/or anti-cancer chemotherapeutic agents,
1 5 - injuries after irradiation of a tissue of the mammal by radio-elements, and
- cachexia.
The present invention also relates to various processes and methods
for making the novel ptendine derivatives defined in general formula (I), as
well as their pharmaceutical^ acceptable salts, N-oxides, solvates,
20 enantiomers and/or dihydro- and tetrahydroderivatives
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1 and 2 represent alternative schemes for preparing 2,4,6-
trisubstituted ptendine derivatives used in this invention.
25 Figure 3 represents a scheme for preparing 2,4,7-trisubstituted
pteridine derivatives used in this invention.
Figure 4 represents a scheme for preparing unsymmetrical 2,4,6-
tnsubstituted pteridines and 2,4,7-trisubstituted pteridines used in this
invention.
30 Figure 5 represents a scheme for preparing symmetrical 2,4,6-
trisubstituted pteridines and 2,4,7-trisubstituted pteridines used in this
invention.
12
DEFINITIONS
Unless otherwise stated herein, the term " trisubstituted " means that
three of the carbon atoms being in positions 2, 4 and 6 or, alternatively, in
positions 2, 4 and 7 of the pteridine ring (according to standard atom
numbering for the pteridine ring) are substituted with an atom or group other
than hydrogen. The term " tetrasubstituted " means that all four carbon atoms
being in positions 2, 4, 6 and 7 of the pteridine ring are substituted with an
atom or group other than hydrogen.
As used herein with respect to a substituting radical, and unless
otherwise stated, the terms " Ci_ 7 alkyl" or " aliphatic saturated hydrocarbon
radicals with 1 to 7 carbon atoms " means straight and branched chain
saturated acyclic hydrocarbon monovalent radicals having from 1 to 7 carbon
atoms such as, for example, methyl, ethyl, propyl, n-butyl, 1-methylethyl
(isopropyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (ter-butyl), 2-methyl-
butyl, n-pentyl, dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, n-
heptyl and the like; the term " Cm alkyl " designate the corresponding radicals
with only 1 to 4 carbon atoms, and so on.
As used herein with respect to a substituting radical, and unless
otherwise stated, the term Ci_ 7 alkylene means the divalent hydrocarbon
radical corresponding to the above defined Ci_ 7 alkyl, such as methylene,
bis(methylene), tns(methylene), tetramethylene, hexamethylene and the like.
As used herein with respect to a substituting radical, and unless
otherwise stated, the terms " Ca-io cydoalkyl" and " cycloaliphatic saturated
hydrocarbon radical with 3 to 10 carbon atoms " means a monocyclic
saturated hydrocarbon monovalent radical having from 3 to 10 carbon atoms,
such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cydohexyl,
cycloheptyl, cyclooctyl and the like, or a C?-to polycyclic saturated hydrocarbon
monovalent radical having from 7 to 10 carbon atoms such as, for instance,
norbomyl, fenchyl, trimethyltricydoheptyl or adamantyl.
As used herein with respect to a substituting radical, and unless
otherwise stated, the term " C3.10 cydoalkylene" means the divalent
hydrocarbon radical corresponding to the above defined C3-10 cycloalkyl.
13
As used herein with respect to a substituting radical, and unless
otherwise stated, the terms " aryl " and "aromatic substituent " are
interchangeable and designate any mono- or polyaromatic monovalent
hydrocarbon radical having from 6 up to 30 carbon atoms such as but not
5 limited to phenyl, naphthyl, anthracenyl, adamantyl, phenantracyl,
fluoranthenyl, chrysenyl, pyrenyl, biphenylyl, terphenyl, picenyl and the like,
including spiro hydrocarbon radicals and fused benzo - C M cycloalkyl radicals
(the latter being as defined above) such as, for instance, indanyl, 1,2,3,4-
tetrahydronaphtalenyl, fluorenyl and the like.
10 As used herein with respect to a substituting radical such as the
combination of R3 and R4, and unless otherwise stated, the term " homo-
cyclic" means a mono- or polycyclic, saturated or mono-unsaturated or
polyunsaturated hydrocarbon radical having from 4 up to 15 carbon atoms but
including no heteroatom in the said ring.
15 As used herein with respect to a substituting radical, and unless
otherwise stated, the term " heterocyclic " means a mono- or polycyclic,
saturated or mono-unsaturated or polyunsaturated monovalent hydrocarbon
radical having from 2 up to 15 carbon atoms and including one or more
heteroatoms in a 3 to 10 membered ring (and optionally one or more
20 heteroatoms attached to one or more carbon atoms of said ring, for instance
in the form of a carbonyl or thiocarbonyl group) and/or to one or more
heteroatoms of said ring, for instance in the form of a sulfone, sulfoxide, N-
oxide, phosphate, phosphonate or selenium oxide, each said heteroatom
being independently selected from the group consisting of nitrogen, oxygen,
25 sulfur, selenium and phosphorus, including benzo-fused heterocyclic radicals,
such as but not limited to dibenzothiophenvl, dibenzofuranyl, oxazolinyl,
oxazolonyl, azaindolyl, azolonyl, thiazolinyl, thiazolonyl, thiazolidinyl, thiazanyl,
pyrimidonyl, thiopyrimidonyl, thiamorpholinyl, azlactonyl, naphtindazolyl,
naphtindolyl, naphtothiazolyl, naphtothbxolyl, naphtoxindolyl. naphtotriazolyl,
30 naphtopyranyl, oxabicycloheptyl, azabenzimidazolyl, azacydoheptyl, aza-
cyclooctyl, azacyclononyl, azabicyclononyl, tetrahydroforyl, tetrahydropyranyl,
tetrahydropyronyl, tetrahydroquinoleinyl, tetrahydrothienyl and dioxide thereof,
dihydrothienyl dioxide, dioxindolyl, dioxinyl, dioxenyl, dioxazinyl, thioxanyl,
14
thioxolyl, thiourazolyl, thiotnazolyl, thiopyranyl, thiopyranyl, coumarinyl,
quinoleinyl, oxyquinoleinyl, quinuclidinyl, xanthinyl, dihydro-pyranyl,
benzodihydrofuryl, benzothiopyronyl, benzothiopyranyl, benzoxazinyl,
benzoxazolyl, benzodioxolyl, benzodioxanyl, benzothiadiazolyl, benzotriazinyl,
benzothiazolyl, benzoxazolyl, phenothioxinyl, phenothiazolyl, phenothienyl
(benzothiofuranyl), phenopyronyl, phenoxazolyl, pyridinyl, dihydropyridinyl,
tetrahydropyridinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrazinyl,
pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, benzotriazolyl, tetrazolyl,
imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, oxadiazolyl,
pyrrolyl, furyl, dihydrofuryl, furoyl, hydantoinyl, dioxolanyl, dioxolyl, dithianyl,
dithienyl, dithifnyl, thienyl, indolyl, indazolyl, benzofuryl, quinolyl, quinazolinyl,
quinoxalinyl, carbazolyl, phenoxazinyl, phenothiazinyl, xanthenyl, purinyl,
benzothienyl, naphtothienyl, thianthrenyl, pyranyl, pyronyl, benzopyronyl,
isobenzofuranyl, chromenyl, phenoxathiinyl, indolizinyl, quinolizinyl,
isoqumolyl, phthalazinyl, naphthiridinyl, cinnolinyl, pteridinyl, carbolinyl,
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, imidazolinyl,
imidazolidinyl, benzimidazolyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,
piperazinyl, uridinyl, thymidinyl, cytidmyl, azirinyl, azindinyl, diazirinyl,
diaziridinyl, oxiranyl, oxaziridinyl, dioxiranyl, thiiranyl, azetyl, dihydroazetyl,
azetidinyl, oxetyl, oxetanyl, thietyl, thietanyl, diazabicyclooctyl, diazetyl,
diaziridinonyl, diaziridinethionyl, chromanyl, chromanonyl, thiochromanyl,
thiochromanonyl, thiochromenyl, benzofuranyl, benzisothiazolyl, benzocarb-
azolyl, benzochromonyl, benzisoalloxazinyl, benzocoumarinyl, thiocoumarinyl,
phenometoxazinyl, phenoparoxazinyl, phentriazinyl, thiodiazinyt, thiodiazolyl,
indoxyl, thio-indoxyl, benzodiazinyl (e.g. phtalazinyl), phtalidyl, phtalimidinyl,
phtalazonyl, alloxazinyl, dibenzopyronyl (i.e. xanthonyl), xanthionyl, isatyl,
isopyrazolyl, isopyrazolonyl, urazolyl, urazinyl, uretinyl, uretidinyl, succinyl,
succimmido, benzylsultimyl, benzylsultamyl and the like, including all possible
isomeric fonms thereof, wherein each carbon atom of the said ring may be
substituted with a substituent selected from the group consisting of halogen,
nitro, C1-7 alkyl (optionally containing one or more functions or radicals
selected from the group consisting of carbonyl (oxo), alcohol (hydroxyl), ether
(alkoxy), acetal, amino, imino, oximino, alkyloximino, amino-atid, cyano,
15
carboxylic acid ester or amide, nitro, thio C1.7 alkyl, thio C3-10 cycloalkyl. C1-7
alkylamino, cydoalkylamino, alkenylamino, cycloalkenylamino, alkynylamino,
arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino,
heterocyclic amino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl,
5 sulfonamide and halogen), C3.7 alkenyl, C2-7 alkynyl, halo C1.7 alkyl, C3.10
cycloalkyl. aryl, arylalkyl. alkylaryl, alkylacyl. arylacyl, hydroxyl, amino, C1-7
alkylamino, cydoalkylamino, alkenylamino, cydo-alkenylamino. alkynylamino,
arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, hetero-
cyclic amino, hydrazino, alkylhydrazino, phenylhydrazino, sulfhydryl, C1-7
10 alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy. oxyheterocydic, heterocydic-
substituted alkyloxy, thio C1-7 alkyl, thio C3-10 cydoalkyl, thioaryl,
thioheterocydic, arylalkylthio, heterocydic-substituted alkylthio, formyl,
hydroxylamino, cyano, carboxylic add or esters or thioesters or amides
thereof, thiocarboxylic add or esters or thioesters or amides thereof;
15 depending upon the number of unsaturations in the 3 to 10 membered ring,
heterocydic radicals may be sub-divided into heteroaromatic (or " heteroaryl")
radicals and non-aromatic heterocydic radicals, when a heteroatom of the
said non-aromatic heterocydic radical is nitrogen, the latter may be
substituted with a substituent seleded from the group consisting of C1.7 alkyl,
20 Ca.10 cydoalkyl, aryl, arylalkyl and alkylaryl.
As used herein with resped to a substituting radical, and unless
otherwise stated, the terms " C1-7 alkoxy ", "Ca-io cydoalkoxy ", " aryloxy",
"arylalkyloxy ", " oxyheterocydic ", "thio C1.7 alkyl", " thio C3.10 cydoalkyl ",
"arylthio ", " arylalkylthio " and " thioheterocydic" refer to substituents
25 wherein a C1-7 alkyl radical, respectively a Cwo cydoalkyl, aryl, arylalkyl or
heterocydic radical (each of them such as defined herein), are attached to an
oxygen atom or a sulfur atom through a single bond, such as but not limited to
methoxy, ethoxy, propoxy. butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy,
mercaptobenzyl, cresoxy and the like.
30 As used herein with resped to a substituting atom, and unless
otherwise stated, the term halogen means any atom selected from the group
consisting of fluorine, chlorine, bromine and iodine.
16
As used herein with respect to a substituting radical, and unless
otherwise stated, the term " halo C1.7 alkyl " means a C1.7 alkyl radical (such
as above defined) in which one or more hydrogen atoms are independently
replaced by one or more halogens (preferably fluorine, chlorine or bromine),
5 such as but not limited to difluoromethyl, trifluoromethyl, trifluoroethyl,
octafluoropentyl, dodecafluoroheptyl, dichloromethyl and the like; the term
"halo C1.4 alkyl " designate the corresponding radical with only 1 to 4 carbon
atoms, and so on.
As used herein with respect to a substituting radical, and unless
10 otherwise stated, the terms " C2-7 alkenyl " and " aliphatic unsaturated
hydrocarbon radical with 2 to 7 carbon atoms " are interchangeable and
designate a straight and branched acyclic hydrocarbon monovalent radical
having one or more ethylenical unsaturations and having from 2 to 7 carbon
atoms such as, for example, vinyl, 2-propenyl. 3-butenyl, 2-butenyl, 2-
15 pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-hexenyl, 2-heptenyl,
butadienyl, pentadienyl, hexadienyl, heptadienyl, heptatrienyl and the like,
including all possible isomers thereof; the term " C3-7 alkenyl " designate the
corresponding radical with only 3 to 7 carbon atoms, and so on.
As used herein with respect to a substituting radical, and unless
20 otherwise stated, the terms " C3-10 cycloalkenyl" and " cycloaliphatic
unsaturated hydrocarbon radical with 3 to 10 carbon atoms " are
interchangeable and mean a monocyclic mono- or polyunsaturated
hydrocarbon monovalent radical having from 3 to 8 carbon atoms, such as for
instance cyclopropenyl, cyclobutenyl, cyclopentenyl, cydopentadienyl,
25 cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cydohepta-
trienyl, cyclooctenyl, cyclooctadienyl and the like, or a C7-10 polycydic mono-
or polyunsaturated hydrocarbon mono-valent radical having from 7 to 10
carbon atoms such as dicydopentadienyl, fenchenyl (induding all isomers
thereof, such as a-pinolenyl), bicydo[2.2 1]hept-2-enyl, bicyclo[2.2.1]hepta-
30 2,5-dienyl, cydo-fenchenyl and the like.
As used herein with resped to a substituting radical, and unless
otherwise stated, the term " C2-7 alkynyl " defines straight and branched chain
hydrocarbon radicals containing one or more triple bonds and having from 2 to
17
20 carbon atoms such as, for example, acetylenyl, 2-propynyl, 3-butynyl, 2-
butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-hexynyl and
the like and all possible isomers thereof.
As used herein with respect to a substituting radical, and unless
5 otherwise stated, the terms " arylalkyl " and "heterocyclic-substituted alkyl"
refer to an aliphatic saturated hydrocarbon monovalent radical, preferably a
C1-7 alkyl or a C3.10 cycloalkyl such as defined above, onto which an aryl
radical or respectively a heterocyclic radical (such as defined above) is
already bonded, such as but not limited to benzyl, pyridylmethyl, pyridylethyl,
10 2-(2-pyridyl)isopropyl, oxazolylbutyl, 2-thienylmethyl and 2-furylmethyl.
As used herein with respect to a substituting radical, and unless
otherwise stated, the term " alkylaryl " and "alkyl-substituted heterocyclic"
refer to an aryl radical or respectively a heterocyclic radical (such as defined
above) onto which is (are) already bonded one or more aliphatic saturated
15 hydrocarbon monovalent radicals, preferably C1.7 alkyl radicals or C3.10
cycloalkyl radicals as defined above such as, but not limited to, o-toluyl, m-
toluyl, p-toluyl, mesityl and 2,4,6-trimethylphenyl.
As used herein with respect to a substituting radical, and unless
otherwise stated, the terms " alkylamino ", "cycloalkylamino ", "alkenyl-
20 . amino", " cycloalkenylamino " , " arylamino ", "arylalkylamino", "heterocyclic
amino " , " hydroxyalkylamiho ", "mercaptoalkylamino " and " alkynylamino"
mean that respectively one (thus monosubstituted amino) or even two (thus
disubstituted amino) Cur alkyl, C^o cycloalkyl, C2-7 alkenyl, C3-10 cycloalkenyl,
aryl, arylalkyl, heterocyclic, mono- or polyhydroxy C1-7 alkyl, mono- or
25 polymercapto C1.7 alkyl or C2-7 alkynyl radical(s) (each of them as defined
herein, respectively) is/are attached to a nitrogen atom through a single bond
or, in the case of heterocyclic, include a nitrogen atom, such as but not limited
to, anilino, benzylamino, methylamino, dimethylamino, ethylamino,
diethylamino, isopropylamino, propenylamino, n-butylamino, ter-butylamino,
30 dibutylamino, morpholino-alkylamino, morpholinyi, piperidinyl, piperazinyl,
hydroxymethylamino, p-hydroxyethylamino and ethynylamino; this definition
also includes mixed disubstituted amino radicals wherein the nitrogen atom is
attached to two such radicals belonging to two different sub-set of radicals,
18
e.g an alkyl radical and an alkenyl radical, or to two different radicals within
the same sub-set of radicals, e.g. methylethylammo; the term " C3.7 alkyl-
amino" designates the corresponding radical with only 3 to 7 carbon atoms in
the alkyl group(s) attached to nitrogen, for instance di-isopropylamino, and so
5 on; among disubstituted amino radicals, symetrically substituted are usually
preferred and more easily accessible.
As used herein with respect to a substituting radical, and unless
otherwise stated, the terms "(thio)carboxylic add ester " , " (thio)carboxylic
acid thioester " and " (thio)carboxylic add amide" refer to radicals wherein the
10 carboxyl or thiocarboxyl group is directly attached to the pteridine ring (e.g. in
the 6- and/or 7-position) and wherein said carboxyl or thiocarboxyl group is
bonded to the hydrocarbonyl residue of an alcohol, a thiol, a polyol, a phenol,
a thiophenol, a primary or secondary amine, a polyamine, an amino-alcohol or
ammonia, the said hydrocarbonyl residue being selected from the group
15 consisting of alkyl, alkenyl, alkynyl, cydoalkyl, cydoalkenyl, aryl, arylalkyl,
alkylaryl, alkylamino, cydoalkylamino, alkenylamino, cydoalkenylamino,
arylamino, arylalkylamino, heterocydic amino, hydroxyalkylamino, mercapto-
alkylamino or alkynylamino (such as above defined, respectively).
As used herein with respect to a substituting radical, and unless
20 otherwise stated, the term " amino-add " refers to a radical derived from a
molecule having the chemical formula H 2 N-CHR--COOH, wherein R is the
side group of atoms characterizing the amino-add type; said molecule may be
one of the 20 naturally-occurring amino-acids or any similar non naturally-
occurring amino-add.
25 As used herein and unless otherwise stated, the term " stereoisomer "
refers to all possible different isomeric as well as conformational forms which
the pteridine derivatives having the general formula (I) may possess, in
particular all possible stereochemical^ and conformationally isomeric forms,
all diastereomers, enantiomers and/or contemners of the basic molecular
30 structure. Some compounds of the present invention may exist in different
tautomeric forms, all of the latter being induded within the scope of the
present invention.
19
As used herein and unless otherwise stated, the term " enantiomer "
means each individual optically active form of a compound of the invention,
having an optical purity or enantiomeric excess (as determined by methods
standard in the art) of at least 80% (i.e at least 90% of one enantiomer and at
most 10% of the other enantiomer), preferably at least 90% and more
preferably at least 98%.
As used herein and unless otherwise stated, the term " solvate "
includes any combination which may be formed by a pteridine derivative of
this invention with a suitable inorganic solvent (e.g. hydrates) or organic
solvent, such as but not limited to alcohols, ketones, esters and the like.
As used herein and unless otherwise stated, the terms " dihydro-
pteridine derivative " and " tetrahydropteridine derivative " refer to the
hydrogenation products of the pteridine denvatives having the general formula
(I), i.e. derivatives wherein two hydrogen atoms are present in positions 5 and
6, or 7 and 8, of the ptendine nng, or respectively wherein four hydrogen
atoms are present in positions 5, 6, 7 and 8 of the said ring; such
hydrogenated derivatives are easily accessible from the pteridine derivatives
of formula (I) by using hydrogenation methods well known in the art.
DETAILED DESCRIPTION OF THE INVENTION
A main object of the invention is to provide a treatment for a class of TNF-a-
related disorders in a mammal, the said disorders being selected from the group
consisting of:
- septic or endotoxic shock,
- TNF-<j-mediated diseases,
- pathologies and conditions associated with and/or induced by abnormal
levels of TNF-a occurring in a systemic, localized or particular tissue type
or location in the body of the mammal,
- toxic effects of TNF-a and/or other anti-cancer chemotherapeutic agents,
- injunes after irradiation of a tissue of the mammal by radio-elements, and
- cachexia.
20
This is achieved by manufacturing a medicament, or a pharmaceutical
composition, including a pteridine derivative having the above mentioned
general formula (I) as a biologically active ingredient
According to the invention, the active pteridine derivatives are as
defined in the general formula (I), wherein each of the substituents X, Z, R 1t
R2. R3 and R4 may correspond to any of the definitions given above (and,
when X includes sulfur, wherein m may be 0, 1 or 2), in particular with any of
the individual meanings (such as illustrated above) of generic terms such as,
but not limited to, "C.7 alkyl ", " C 27 alkenyl ", - C 2 - 7 alkynyl ", " aryl ",
"alkylaryl ", "arylalkyl ", "alkylamino", " cycloalkylamino ", "alkenylamino
"alkynylamino", "arylammo", " arylalkylamino ", " C1.7 alkoxy", " C3.10
cycloalkoxy ", "thio C1.7 alkyl ", " thio C3.10 cycloalkyl ", - halo C1-7 alkyl ",
"amino-add " and the like In particular, the pteridine derivatives wherein R2 is
C3.7 alkylamino and/or wherein R4 is a heterocyclic radical other than
piperidinyl, morpholinyl or pyrrolidinyl (i.e. R4 is for instance selected from the
group consisting of dibenzothiophenyl, dibenzofuranyl, oxazolinyl, oxazolonyl,
azaindolyl, azolonyl, thiazolinyl, thiazolonyl, thiazolidinyl, thiazanyl,
pyrimidonyl, thiopyrimidonyl, azlactonyl, naphtindazolyl, naphtindolyl,
naphtothiazolyl, naphtothioxolyl, naphtoxindolyl, naphtotriazolyl, naphto-
pyranyl, oxabicydoheptyl, azabenzimidazolyl, azacycloheptyl, azacydooctyl
dihydrothienyl dioxide, dioxindolyl, dioxinyl, dioxenyl, dioxazinyl, thioxanyl,
thioxolyl, thiourazolyl, thiotriazolyl, thiopyranyl, thiopyronyl, coumarinyl, quino-
leinyl, oxyquinoleinyl, quinudidinyl, xanthinyl, dihydropyranyl, benzodihydro-
furyl, benzothiopyronyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl,
benzodioxolyl, benzodioxanyl, benzothiadiazolyl, benzotriazinyl,
benzothiazolyl, benzoxazolyl, phenothioxinyl, phenothiazolyl, phenothienyl,
phenopyronyl, phenoxazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl,
thiomorpholinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl,
benzotriazolyl, tetrazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl,
isothiazolyl, oxazolyl, oxadiazolyl, pyrrolyl, furyl, dihydrofuryl, furoyl,
hydantoinyl, dioxolanyl, dioxolyl, dithianyl, dithienyl, dithiinyl, thienyl, indolyl,
indazolyl, benzofuryl, quinolyl, quinazolinyl, quinoxalinyl, azacydononyl,
azabicydononyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydropyronyl,
21
tetrahydroquinoleinyl, tetrahydrothienyl and dioxide thereof, carbazolyl,
phenoxazinyl, phenothiazinyl, xanthenyl, purinyl, benzothienyl, naphtothienyl,
thianthrenyl, pyranyl, pyronyl, benzopyronyl, isobenzofuranyl, chromenyl,
phenoxathiinyl, indolizinyl, quinolizinyl, isoquinolyl, phthalazinyl, naphthiridinyl,
cinnolinyl, pteridinyl, carbolinyl, acridinyl, perimidinyl, phenarrthrolinyl,
phenazinyl, phenothiazinyl, imidazolinyl, imidazolidinyl, benzimidazolyl,
pyrazolinyl, pyrazolidinyl, pyrrolinyl, piperazinyl, uridinyl, thymidinyl, cytidinyl.
azirinyl, aziridinyl, diazirinyl, diaziridinyl, oxiranyl, oxaziridinyl, dioxiranyl,
thiiranyl, azetyl, dihydroazetyl, azetidinyl, oxetyl, oxetanyl, thietyl, thietanyl,
diazabicyclooctyl, diazetyl, diaziridinonyl, diaziridinethionyl, chromanyl,
chromanonyl, thiochromanyl, thiochromanonyl, thiochromenyl, benzofuranyl,
benzisothiazolyl, benzocarbazolyl, benzochromonyl, benzisoalloxazinyl,
benzocoumarinyl, thiocoumarinyl, phenometoxazinyl, phenoparoxazinyl,
phentriazinyl, thiodiazinyl, thiodiazolyl, indoxyl, thioindoxyl, benzodiazinyl,
phtalidyl, phtalimidinyl, phtalazonyl, alloxazinyl, dibenzopyronyl, xanthionyl,
isatyl, isopyrazolyl, isopyrazolonyl, urazolyl, urazinyl, uretinyl, uretidinyl,
succinyl, succinimido, benzylsultimyl and benzylsultamyl) are novel
compounds which were never suggested for use in medicine.
When a mixture of enantiomers of a pteridine derivative having the
general formula (I) according to the invention is obtained during synthesis, the
said mixture may be separated by means and methods standard in the art,
e.g. liquid chromatography using one or more suitable chiral stationary
phases. The latter include, for example, polysaccharides, in particular
cellulose or amylose derivatives. Commercially available polysaccharide-
based chiral stationary phases suitable for this purpose are ChiralCel™ CA,
OA, OB, OC, OD, OF, OG, OJ and OK, and Chiralpak™ AD, AS, OP(+) and
OT(+). Appropriate eluents or mobile phases for use in combination with said
polysaccharide-based chiral stationary phases are hydrocarbons such as
hexane and the like, optionally admixed with an alcohol such as ethanol,
isopropanol and the like. The above mixture of enantiomers may alternatively
be separated by forming diastereoisomers, followed by separation of the
diastereoisomers, e.g. by differential crystallization or chromatography. The
22
resolving agent may be cleaved from the separated diastereoisomers, e.g. by
treatment with acids or bases, in order to generate the pure enantiomers of
the compounds of the invention.
Some preferred pteridine derivatives having the general formula (I)
5 according to the invention are more specifically illustrated in the following
examples For instance, useful pteridine species disclosed below include
these wherein:
- Ri is selected from the group consisting of methyl, ethyl, isopropyl, pentyl
and benzyl, and/or
10 - • R 2 is amino, and/or
- R4 is hydrogen or methoxy, and/or
- R3 is 3-thienyl or 2-thienyl or a phenyl group with one or more substituents
(in the latter case, such substituents are preferably each independently
selected from the group consisting of fluoro, methoxy, ethoxy,
15 trifluoromethyl, dimethyl-amino, chloro. cyano, methyl, ethyl,
carboxymethyl, methylthio, dimethylcarboxamido, diethylcarboxamido and
methylcarboxylate, and/or
- X is a sulfur atom (i.e. m is 0) or an oxygen atom, or
- X is NZ, wherein Z is selected from the group consisting of hydrogen,
20 methyl, ethyl, isopropyl and benzyl, or NZ together with R, forms a radical
selected from the group consisting of hydroxylamino, tetrahydropyndinyl,
morpholinyl, piperidinyl, piperazinyl, N-methylpiperazinyl. 1,2,4-triazolyl
and pyrrolidinyl
The present invention further provides processes and methods for making
25 the pteridine derivatives having the general formula (I). As a general rule, the
preparation of these compounds is based on the principle that, starting from a
suitable pteridine precursor, each of the substituents XRi , R 2 , R3 and R4may
be introduced separately (except, of course, when R3 together with R4 forms a
homocyclic or heterocyclic radical) without adversely influencing the presence
30 of one or more substituents already introduced at other positions on the
pteridine ring or the capacity to introduce further substituents later on.
Methods of manufacture have been developed by the present inventors
which may be used alternatively to, or may be combined with, the methods of
23
synthesis already known in the art of pteridine derivatives (depending upon
the targeted final compound). For instance, methods for simultaneously
introducing R3 and R4 in the form of a homocyclic or heterocyclic radical at
positions 6 and 7 of the pteridine ring are already known from U.S. Patent No.
5 2,581 ,889. The synthesis of mono- and di-/V-oxides of the pteridine derivatives
of this invention can easily be achieved by treating the said derivatives with an
oxidizing agent such as, but not limited to, hydrogen peroxide (e.g. in the
presence of acetic acid) or a peracid such as chloroperbenzoic acid. Dihydro-
and tetrahydropteridine derivatives of this invention can easily be obtained by
10 catalytic hydrogenation of the corresponding pteridine derivatives, e.g. by
placing the latter in a hydrogen atmosphere in the presence of platinum oxide
or platinum. The methods for making the pteridine derivatives of the present
invention will now be explained in more details by reference to the appended
figures 1 to 5 wherein, uniess otherwise stated hereinafter, each of the
1 5 substituting groups or atoms X, Z, R 1( R 2l R 3 and R4 is as defined in formula (I)
of the summary of the invention and, more specifically, may correspond to any
of the individual meanings disclosed above. The same manufacturing
methods may also be applied, if need be, while starting from pteridine
derivatives which are already known in the art. In the description of the
20 reaction steps involved in each figure, reference is made to the use of certain
catalysts and/or certain types of solvents. It should be understood that each
catalyst mentioned should be used in a catalytic amount well known to the
skilled person with respect to the type of reaction involved. Solvents that may
be used in the following reaction steps include various kinds of organic
25 solvents such as protic solvents, polar ^p^otic solvents and non-polar solvents
as well as aqueous solvents which are inert under the relevant reaction
conditions. More specific examples include aromatic hydrocarbons,
chlorinated hydrocarbons, ethers, aliphatic hydrocarbons, alcohols, esters,
ketones, amides, water or mixtures thereof, as well as supercritical solvents
30 such as carbon dioxide (while performing the reaction under supercritical
conditions). The suitable reaction temperature and pressure conditions
applicable to each kind of reaction step will not be detailed herein but do not
depart from the relevant conditions already known to the skilled person with
24
respect to the type of reaction involved and the type of solvent used (in
particular its boiling point).
Figure 1 represents a scheme for the preparation of 2,4,6-trisubstituted
pteridines with various R 2 and R3 substituents in the 2- and 6-positions of the
pteridine ring. In the first step (a), a chloropyrimidine 1, wherein R 2 may be
inter alia amino, alkylamino, arylamino, alkoxy, aryloxy, mercaptoalkyl, or
mercaptoaryl, is reacted with an appropriate nucleophile R^H, the said
nucleophile being selected from the group consisting of alcohols (e.g.
methanol, ethanol, isopropanol or benzylalcohol), thiols, primary amines and
secondary amines wherein R t may be inter alia alkyl, cycloalkyl, aryl, alkylaryl,
heteroaryl or alkylheteroaryl. Introduction of a nitroso group into the pyrimidine
intermediate 2 occurs in step (b) under acidic aqueous conditions in the
presence of sodium nitrite NaN0 2 . Reduction of the nitroso functionality of the
pynmidine intermediate 3 into a free amino group in intermediate 4 is then
effected in step (c) by means of reducing agents (such as Na2S 2 0 4 or
(NH 4 ) 2 S) in water, or catalytically (Pt/H 2 ) in the presence of a protic solvent In
step (d), ring closure is performed by treating the diaminopyrimidine 4 with
glyoxal in order to form a pteridine ring. In step (e), the nitrogen atom at
position 8 of the pteridine ring of compound 5 is oxidized, e.g. using Kb0 2
under acidic conditions. In step (f), a chlorine atom is regioselectively
introduced on the 6 position of the pteridine ring of compound 6 by treatment
with a carboxylic acid choride such as acetyl chloride under acidic conditions.
Then in step (g) the 6-chlorosubstituted pteridine 7 is reacted with a boronic
acid having the general formula R3B(OH) 2 , wherein R3 may be alkyl,
cycloalkyl, aryl or heteroaryl, under basic conditions (such as in the presence
of an aqueous alcaline solution) and a palladium based catalyst, thus yielding
the desired derivative 8 of the present invention.
Figure 2 represents a scheme for the preparation of 2,4,6-trisubstituted
pteridines with various R 2 and R3 substituents in the 2- and 6-positions of the
ptendine ring. In step (a), a nitroso group is introduced in position 5 of the
pyrimidine ring of a compound 9, wherein R 2 may be inter alia amino,
alkylamino or arylamino, using sodium nitrite under aqueous acidic conditions.
Reduction of the nitroso group of compound 10 in step (b) is achieved either
25
catalytically (Pt/H 2 ) in the presence of a protic solvent, or chemically using
sodium dithionite or ammonium sulfide in the presence of water. Then in the
next step (c), the condensation of the diaminopynmidine 11 with an a-
ketoaldoxime bearing the group R3, wherein R3 may be alkyl, cycloalkyl, aryl
5 or heteroaryl, under acidic conditions in the presence of a protic solvent such
as methanol, regioselectively yields the 6-substituted pteridine derivative 12.
Activation of the hydroxyl group of the tautomeric form of 12 by a nucleophilic
displacement reaction occurs by preparing the 4-R1 ,2,4)-triazolyl] pteridine
derivative 13, using POCI 3 or 4-chlorophenyl phosphorodichloridate, and
10 1,2,4-triazole in the presence of e.g. pyridine as solvent. If R 2 is a free amino
group, protection of R 2 e.g. by means of an acetyl group may be necessary
before carrying out the reaction of step (d), followed by a deprotection of the
acetyl group during the nucleophilic displacement reaction. The nucleophilic
substitution in step (e) may be performed, e.g. in the presence of 1,4-dioxane
15 as a solvent, by mixing the pteridine derivative 13 at room temperature with an
appropriate nucleophile RiXH, the said nudeophile being selected from the
group consisting of alcohols (e.g. methanol, ethanol, isopropanol or
benzylalcohol), thiols, primary amines and secondary amines wherein R t may
be inter alia alkyl, cycloalkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl, thus
20 yielding the desired derivative 14 of the present invention.
Figure 3 represents a scheme for the preparation of 2,4,7-trisubstrtuted
pteridines with various R 2 and R« substituents in the 2- and 7-positions of the
pteridine ring. In reaction step (a), a tetraaminopyrimidine 15, wherein R 2 may
be inter alia amino, alkylamino or arylamino, is reacted with inter alia an
25 alkylglyoxal, arylglyoxal, alkylarytglyoxal, heteroarylglyoxal or alkyl
heteroarylglyoxat in water under basic conditions, yielding the 7-substituted
pteridine derivative 16 wherein R4 may be inter alia alkyl, cycloalkyl, aryl,
heteroaryl, alkylaryl or alkylheteroaryl. In step (b), hydrolysis under reflux in
the presence of sodium hydroxide 1N yielded the 4-hydroxy tautomer of
30 pteridine derivative 17. In step (c), a 1 ,2,4-triazolyl group is introduced in
position 4 by reacting 17 with triazole in the presence of 4-chlorophenyl
phosphorodichloridate and dry pyridine. Finally in reaction step (d). the 1,2,4-
triazolyl group at position 4 of the pteridine derivative 18 is displaced by an
26
appropriate nudeophie RiXH, the said nucleophile being selected from the
group consisting of alcohols (e.g. methanol, ethanol, isopropanol or
benzylalcohol), thiols, priman/ amines and secondary amines wherein Ri may
be inter alia alkyl, cycloalkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl, in the
5 presence of a polar aprotc or protic solvent, thus yielding the desired
derivative 19 of the present invention.
Figure 4 represents a scheme for the synthesis of unsymmetrical 2,4,6-
trisubstituted and 2,4,7-tnsubstituted pteridine derivatives with various R 2 , R 3
and R4 substituents in the 2-, 6- and 7-positions of the pteridine ring. In step
10 (a), the thiol function on 2-mercapto-4,6-diaminopyrimidine is methylated, e.g.
by reaction with methyl iodide in the presence of a solvent such as ethanol, in
order to yield 2-thiomethyl-4,6-diaminopyrimidine. Introduction of a nitroso
group in the 5-position of the pyrimidine ring is then achieved in step (b) by
using sodium nitrite under aqueous acidic conditions. In the next step (c), the
15 methylthio group in the 2-position is exchanged for a group R 2 , wherein R 2
may be inter alia alkoxy, aryloxy, cycloalkyloxy, heteroaryloxy, mercaptoalkyl,
mercaptoaryl, mercaptocyclo-alkyl or mercaptoheteroaryl by reaction with an
appropriate nucleophile. Reduction of the nitroso functionality is then achieved
in step (d) either catalytically {PVH2) in the presence of a protic solvent or
20 chemically using sodium dithionite or ammonium sulfide in the presence of
water. Then in the next step (e), the condensation of the 2-substituted-4,5,6-
triaminopyrimidine with an a-ketoaldoxime bearing the group R3, wherein R3
may be inter alia alkyl, cycloalkyl, aryl or heteroaryl, under acidic conditions in
the presence of a solvent such as methanol, regioselectively yields a 2,6-
25 substttuted-4-aminoptendine derivative. The corresponding 2,7-substituted-4-
ammopteridine can be obtained, according to step (i), by reaction of the 2-
substituted-4,5,6-triaminopyrimidine with a glyoxal bearing the group R4,
wherein R4 may be inter alia alkyl, cycloalkyl, aryl or heteroaryl. According to
step (f), acidic or basic hydrolysis of the amino group at position 4 of the
30 pteridine ring, performed on the derivative from step (e) or (i), yields the
corresponding 4-oxopteridine derivative. In step (g), the hydroxyl group of the
tautomeric form of the latter is activated by nucleophilic displacement, e.g. by
preparing the 4-[(1,2,4)-triazolyl] pteridine derivative Finally, the nucleophilic
27
displacement in step (h) is performed by mixing the said 4-triazolyl pteridine
derivative with the appropriate nucleophile RiXH, wherein Ri may be inter alia
alkyl, cydoalkyl, aryl,' heteroaryl, alkylaryl, alkylheteroaryl.
Figure 5 represents a scheme for the synthesis of symmetrical 2,4,6-
5 ^'substituted and 2,4,7-trisubstituted pteridine derivatives with various R 2 , R3
and R4 substituents in the 2- 6- and 7-positions of the pteridine ring. In step
(a), the pyrimidine ring is nitrated in position 5 under strongly acidic conditions
(HNO3, H2SO4). Then in step (b) both hydroxyl groups (from the tautomeric
form) are converted to chloro groups by treatment with a chlorinating agent
10 such as POCI3 or SOCI 2 . Both chloro substituents are then displaced in step
(c) with an appropriate nucleophile RiXH, wherein R f may be inter alia alkyl,
cydoalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl. The nitro group is
reduced in step (d) to an amino group by treatment with a redudng agent (e.g.
Pt/H 2 ). Finally, reaction of the 2,4-substituted-5,6-diaminopyrimidine from step
15 (d) with an a-ketoaldoxime bearing the group R3, wherein R3 may be inter alia
alkyl, cydoalkyl, aryl or heteroaryl, regioselectively yields the desired 2,4,6-
trisubstituted pteridine derivative in step (e). Alternatively, readion of the 2,4-
substituted-5,6-diaminopyrimidine from step (d) with a glyoxal bearing the
group R4, wherein R4 may be inter alia alkyl, cydoalkyl, aryl or heteroaryl,
20 yields the desired 2,4,7-trisubstituted pteridine derivative in step (f).
When applicable, and depending upon the specific substituents being
present, the pteridine derivatives having the general formula (I) may be in the
form of a pharmaceutically acceptable salt. The latter indude any
therapeutically active non-toxic addition salt which compounds having the
25 general formula (I) are able to form with a salt-forming agent. Such addition
salts may conveniently be obtained by treating the pteridine derivatives of the
invention with an appropriate salt-forming add or base. For instance, pteridine
derivatives having basic properties may be converted into the corresponding
therapeu-tically active, non-toxic add addition salt form by treating the free
30 base form with a suitable amount of an appropiate add following conventional
procedures. Examples of such appropnate salt-forming acids indude, for
instance, inorganic adds resulting in forming salts such as but not limited to
hydrohalides (e.g. hydrochloride and hydrobromide), sulfate, nitrate,
28
phosphate, diphosphate, carbonate, bicarbonate, and the like; and organic
monocarboxylic or dicarboxylic acids resulting in forming salts such as, for
example, acetate, propanoate, hydroxyacetate, 2-hydroxypropanoate, 2-
oxopropanoate, lactate, pyruvate, oxalate, malonate, succinate, maleate,
5 fumarate, malate, tartrate, citrate, methanesulfonate, ethanesulfbnate,
benzoate. 2-hydroxybenzoate, 4-amino-2-hydroxybenzoate, benzenesulfo-
nate, p-toluenesulfbnate, salicylate, p-aminosalicylate, pamoate, bitartrate.
camphorsulfonate, edetate, 1,2-ethanedisulfonate, fumarate. glucoheptonate,
gluconate, glutamate, hexylresorcinate, hydroxynaphtoate, hydroxyethane-
10 sulfonate, mandelate, methylsulfate, pantothenate, stearate, as well as salts
derived from ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)2-
butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxy-butanedioic, 2-hydroxy-
1,2,3-propanetricarboxylic and cyclohexanesulfamic acids and the like.
Pteridine derivatives having acidic properties may be converted in a
15 similar manner into the corresponding therapeutically active, non-toxic base
addition salt form. Examples of appropriate salt-forming bases include, for
instance, inorganic bases like metallic hydroxides such as but not limited to
those of alkali and alkaline-earth metals like calcium, lithium, magnesium,
potassium and sodium, or zinc, resulting in the corresponding metal salt;
20 organic bases such as but not limited to ammonia, alkylamines, benzathine,
hydrabamine, arginine, lysine, N.N'-dibenzylethylenediamine, chloroprocaine,
choline, diethanolamine, ethylene-diamine, N-methylglucamine, procaine and
the like.
Reaction conditions for treating the pteridine derivatives (I) of this
25 invention with an appropriate salWorming acid or base are similar to standard
conditions involving the same acid or base but different organic compounds
with basic or acidic properties, respectively. Preferably, in view of its use in a
pharmaceutical composition or in the manufacture of medicament for treating
specific diseases, the pharmaceutically acceptable salt will be designed, i.e.
30 the salt-forming acid or base will be selected so as to impart greater water-
solubility, lower toxicity, greater stability and/or slower dissolution rate to the
pteridine derivative of this invention.
29
The present invention provides the use of the above-described
pteridine deivatives as biologically-active ingredients, i.e. active principles,
especially as a medicine or a diagnostic agent or for the manufacture of a
medicament or a diagnostic kit for the prevention or treatment of a TNF-a-
related disorder in a mammal. The class of such disorders include the following:
- septic or endotoxic shock or sepsis, especially in patients with a serum
level of interleukin-6 above 1 ,000 pg/ml at start of treatment;
- vascular TNF-a- mediated diseases such as, but not limited to,
disseminated intravascular coagulation and Kawasaki's pathology;
- pathologies and conditions associated with and/or induced by abnormal
levels of TNF-a (herein defined as exceeding by at least 10 % and at
most 500% the TNF-a level present in a normal healthy subject)
occurring in a systemic, localized or particular tissue type or location in
the body of the mammal; such tissue types include, but are not limited
to, blood, lymph, liver, kidney, spleen, heart muscle or blood vessels,
brain or spinal cord white matter or grey matter, cartilage, ligaments,
tendons, lung, pancreas, ovary, testes and prostate. Abnormal TNF
levels can also be localized to specific regions or cells in the body, such
as joints, nerve blood vessel junctions and bones Such pathologies
include alcohol-induced hepatitis, neurodegenerative diseases such as
extrapyramidal and cerebellar disorders including lesions of the
corticospinal system; disorders of the basal ganglia; hyperkinetic
movement disorders such as chorea; drug-induced movement
disorders; hypokinetic movement disorders, such as Parkinson's
disease, spinocerebellar degenerations such as spinal ataxia, multiple
systems degenerations (including Dejerine-Klumpke syndrome) and
systemic disorders (including Refsum's disease, abetalipoprotemia,
ataxia and telangiectasia); disorders of the motor unit, such as
neurogenic muscular atrophies (anterior horn cell degeneration, such
as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and
juvenile spinal muscular atrophy); Alzheimer's disease; Wernicke-
Korsakoff syndrome; Creutzfeldt-Jakob disease; Hallerrorden-Spatz
disease; and primary or secondary myelodysplasia syndromes;
30
- toxic effects of TNF-a and/or anti-cancer chemotherapeutic agents,
especially side effects associated with TNF generation during neoplastic
therapy, for instance following use of cisplatin;
- injuries after irradiation of a tissue of a mammal by radio-elements, such
5 as but not limited to radiation-induced graft-versus^host disease; and
- cachexia and similar chronic wasting diseases, whether associated with
cancer or with other chronic diseases such as malabsortive disorders,
excessive physical stress, eating disorders and AIDS.
The medicament of this invention may be for prophylactic use, i.e. where
10 circumstances are such that an elevation in the TNF level might be expected or
alternatively, may be for use in reducing the TNF level after it has reached an
undesirably high level or as the TNF level is rising.
The medicament according to this invention may be administered orally
or in any other suitable fashion. Oral administration is preferred and the
15 preparation may have the form of a tablet, aqueous dispersion, dispersable
powder or granule, emulsion, hard or soft capsule, syrup, elixir or gel. The
dosing forms may be prepared using any method known in the art for
manufacturing these pharmaceutical compositions and may comprise as
additives sweeteners, flavoring agents, coloring agents, preservatives and the
20 like. Carrier materials and excipients are detailed hereinbelow and may
include, inter alia, calcium carbonate, sodium carbonate, lactose, calcium
phosphate or sodium phosphate; granulating and disintegrating agents,
binding agents and the like. The pharmaceutical composition or combined
preparation of this invention may be included in a gelatin capsule mixed with
25 any inert solid diluent or carrier material, or has the form of a soft gelatin
capsule, in which the ingredient is mixed with a water or oil medium. Aqueous
dispersions may comprise the biologically active composition or combined
preparation in combination with a suspending agent, dispersing agent or
wetting agent Oil dispersions may comprise suspending agents such as a
30 vegetable oil. Rectal administration is also applicable, for instance in the form
of suppositories or gels. Injection (e.g. intramuscularly or intraperiteneously) is
also applicable as a mode of administration, for instance in the form of
31
injectable solutions or dispersions, depending upon the disorder to be treated
and the condition of the patient
Usually the medicament of the invention is in the form of a combination
of the pteridine derivative active principle and one or more pharmaceutically
5 acceptable carriers or excipients
The term " pharmaceutically acceptable carrier or excipient a as used
herein refers to any material or substance with which the active principle, i.e
the pteridine derivative having the general formula (I) may be formulated in
order to facilitate its application or dissemination to the locus to be treated, for
10 instance by dissolving, dispersing or diffusing the said composition, aid/or to
facilitate its storage, transport or handling without impairing its effectiveness.
The pharmaceutically acceptable carrier may be a solid or a liquid or a gas
which has been compressed to form a liquid, i.e. the compositions of this
invention can suitably be used as concentrates, emulsions, solutions,
1 5 granulates, dusts, sprays, aerosols, pellets or powders.
Suitable pharmaceutical earners for use in the said pharmaceutical
compositions and their formulation are well known to those skilled in the art.
There is no particular restriction to their selection within the present invention
although, due to the usually low or very low water-solubility of the pteridine
20 derivatives of this invention, special attention will be paid to the selection of
suitable carrier combinations that can assist in properly formulating them in
view of the expected time release profile. Suitable pharmaceutical earners
include additives such as wetting agents, dispersing agents, stickers,
adhesives, emulsifying or surface-active agents, thickening agents,
25 complexing agents, gelling agents, solvents, coatings, antibacterial and
antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic
agents (such as sugars or sodium chloride) and the like, provided the same
are consistent with pharmaceutical practice, i.e. carriers and additives which
do not create permanent damage to mammals. The pharmaceutical
30 compositions of the present invention may be prepared in any known manner,
for instance by homogeneously mixing, dissolving, spray-drying, coating
and/or grinding the active ingredients, in a one-step or a multi-steps
32
procedure, with the selected carrier material and, where appropriate, the other
additives such as surface-active agents, may also be prepared by
micronisation, for instance in view to obtain them in the form of microspheres
usually having a diameter of about 1 to 10 pm, namely for the manufacture of
5 microcapsules for controlled or sustained release of the biologically active
mgredient(s).
Suitable surface-active agents to be used in the pharmaceutical
compositions of the present invention are non-ionic, cationic and/or anionic
materials having good emulsifying, dispersing and/or wetting properties.
10 Suitable anionic surfactants include both water-soluble soaps and water-
soluble synthetic surface-active agents. Suitable soaps are alkaline or
alkaline-earth metal salts, unsubstituted or substituted ammonium salts of
higher fatty adds (C10-C22), e 9 toe sodium or potassium salts of oleic or
stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or
15 tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic
acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives
and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the
form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or
ammonium salts substituted with an alkyl or acyl radical having from 8 to 22
20 carbon atoms, eg. the sodium or calcium salt of lignosulphonic acid or
dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from
natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or
sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of
fatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazole
25 derivatives preferably contain 8 to 22 carbon atoms. Examples of
alkylarylsulphonates are the sodium, calcium or alcanolamine salts of
dodecylbenzene sulphonic acid or dibutyl-naphtalenesulphonic acid or a
naphtalene-sulphonic acid/formaldehyde condensation product. Also suitable
are the corresponding phosphates, e.g. salts of phosphoric acid ester and an
30 adduct of p-nonylphenol with ethylene and/or propylene oxide, or
phospholipids. Suitable phospholipids for this purpose are the natural
(originating from animal or plant cells) or synthetic phospholipids of the
cephalm or lecithin type such as e.a. Dhosohatidylethanolamine.
33
phosphatidylserine, phosphatidylglycerine, lysoledlhin, cardiolipin, dioctanyl-
phosphatidylcholine, dipalmitoylphoshatidylcholine and their mixtures.
Suitable non-ionic surfactants include polyethoxylated and
polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids,
5 aliphatic amines or amides containing at least 12 carbon atoms in the
molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as
polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated
and unsaturated fatty acids and alkylphenols, said derivatives preferably
containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the
1 0 (aliphatic) hydrocarbon moiety and 6 to 1 8 carbon atoms in the alkyl moiety of
the alkylphenol. Further suitable non-ionic surfactants are water-soluble
adducts of polyethylene oxide with poylypropylene glycol,
ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the
alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups
15 and/or 10 to 100 propyleneglycol ether groups. Such compounds usually
contain from 1 to 5 ethyleneglycol units per propyleneglycol unit.
Representative examples of non-ionic surfactants are nonylphenol-
polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/ polyethylene
oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and
20 octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan
(such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and
pentaerythritol are also suitable non-ionic surfactants.
Suitable cationic surfactants include quaternary ammonium salts,
preferably halides, having 4 hydrocarbon radicals optionally substituted with
25 halo, phenyl, substituted phenyl or hydroxy, for instance quaternary
ammonium salts containing as N-substituent at least one Ce-C^ alkyl radical
(e g cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further
substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-
lower alkyl radicals
JO A more detailed description of surface-active agents suitable for this
purpose may be found for instance in "McCutcheon's Detergents and
Emulsifiers Annual" (MC Publishing Crop., Ridgewood. New Jersey, 1981),
34
"Tensid-Taschenbuch", 2 nd ed. (Hanser Verlag, Vienna, 1981) and
"Encyclopaedia of Surfactants (Chemical Publishing Co., New York, 1981).
Structure-forming, thickening or gel-forming agents may be included into
the pharmaceutical compositions of the invention. Suitable such agents are in
5 particular highly dispersed silicic acid, such as the product commercially
available under the trade name Aerosil; bentonites; tetraalkyl ammonium salts
of montmorillonites (e.g., products commercially available under the trade
name Bentone), wherein each of the alkyl groups may contain from 1 to 20
carbon atoms; cetostearyl alcohol and modified castor oil products (e.g. the
1 0 product commercially available under the trade name Antisettle).
Gelling agents which may be included into the pharmaceutical
compositions of the present invention include, but are not limited to, cellulose
derivatives such as carboxymethylcellulose, cellulose acetate and the like;
natural gums such as arabic gum, xanthum gum, tragacanth gum, guar gum
15 and the like; gelatin; silicon dioxide; synthetic polymers such as carbomers,
and mixtures thereof. Gelatin and modified celluloses represent a preferred
class of gelling agents.
Other optional excipients which may be included in the pharmaceutical
compositions of the present invention include additives such as magnesium
20 oxide; azo dyes; organic and inorganic pigments such as titanium dioxide; UV-
absorbers; stabilisers; odor masking agents; viscosity enhancers; antioxidants
such as, for example, ascorbyl palmitate, sodium bisulfite, sodium
metabisulfite and the like, and mixtures thereof; preservatives such as, for
example, potassium sorbate, sodium benzoate, sorbic acid, propyl gallate,
25 benzylalcohol, methyl paraben, propyl paraben and the like; sequestering
agents such as ethylene-diamine tetraacetic acid; flavoring agents such as
natural vanillin; buffers such as citric acid and acetic acid; extenders or bulking
agents such as silicates, diatomaceous earth, magnesium oxide or aluminum
oxide; densification agents such as magnesium salts; and mixtures thereof.
30 Additional ingredients may be included in order to control the duration of
action of the biologically-active ingredient in the compositions of the invention.
Control release compositions may thus be achieved by selecting appropriate
35
polymer carriers such as for example polyesters, polyamino-acids, polyvinyl-
pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose,
carboxymethylcellulose, protamine sulfate and the like. The rate of drug
release and duration of action may also be controlled by incorporating the
5 active ingredient into particles, e.g. microcapsules, of a polymeric substance
such as hydrogels, polylactic acid, hydroxymethyl-cellutose, polymethyl
methacrylate and the other above-described polymers. Such methods include
colloid drug delivery systems like liposomes, microspheres, microemulsions,
nanoparticles, nanocapsules and so on Depending on the route of
0 administration, the pharmaceutical composition of the invention may also
require protective coatings.
Pharmaceutical forms suitable for injectable use include sterile aqueous
solutions or dispersions and sterile powders for the extemporaneous
preparation thereof. Typical carriers for this purpose therefore include
5 biocompatible aqueous buffers, ethanol, glycerol, propylene glycol,
polyethylene glycol, complexing agents such as cyclodextnns and the like,
and mixtures thereof.
The present invention further relates to a method for preventing or treating
a TNF-a-related disease, such as above defined, in a subject or patient by
> administering to the patient in need thereof an effective amount of a pteridine
derivative having the general formula (I). The effective amount is usually in the
range of 0.01 mg to 20 mg, preferably 0.1 mg to 5 mg, per day per kg
bodyweight for humans. Depending upon the pathologic condition to be
treated and the patient's condition, the said effective amount may be divided
into several sub-units per day or may be administered at more than one day
intervals. The patient to be treated may be any warm-blooded animal such as
a mammal, preferably a human being, suffenng from said TNF-a-related
disease.
The following examples are intended to illustrate several embodiments of
the present invention, including the preparation of the pteridine derivatives,
without limiting its scope in any way.
Example 1 - preparatio n of 2-aminQ^4-n-oentvlow-6-stvrvlDteridine
10
30
36
A mixture of 1.5 g (5.6 mmoles) 2^mino^-chloro-4-n-pentyloxypteridine
(e.g. available following the procedure disclosed by Mohr et al. in Hetv. Chem.
Acta (1992) 75:2317), palladium acetate (63 mg, 0.28 mmoles), tri-o-
tolylphosphane (682 mg, 2.24 mmoles), cuprous iodide (53 mg, 0.28 mmoles),
styrene (1,3 ml., 11.3 mmoles) and triethylamine 3.1 ml, 22 mmoles) was
stirred in dry acetonitrile (50 ml) under reflux for 90 hours. It was evaporated
and the residue purified by silica gel column chromatography with chloroform.
The product fraction was evaporated to give 1.37 g (yield: 72%) of an orange
powder exhibiting, after recrystallization from a EtOAc/hexane mixture, a
melting point (m p.) range of 127-128 °C.
Example 2 - preparation of 2^amino-6-(l 2-dibromoDhfinBthvlM-n-Dentvlnyy-
pteridine .
To a solution of the denvative of example 1 (1.0 g, 2.94 mmoles) in
15 chloroform (50 ml) was added a 2 M bromine solution in chloroform (2.2 ml.,
4.4 mmoles) and then the mixture was stirred at room temperature for 7 hours.
It was diluted with chloroform (50 ml), washed with a saturated aqueous
NazSOa solution (100 ml) and dried over sodium sulfate. After evaporation of
the solvents, the residue was treated with toluene, filtered, washed with ether
and dried in a vacuum desiccator to give 0.84 g (yield: 57%) of a yellow
powder.
Example 3 - preparation of 2-amino-4 7-dimethoxv-6-stvry|rteridine
A suspension of the derivative of example 2 (0.3 g, 0.6 mmoles) is
methanol (10 ml) was treated with 1 M methanol sodium methoxide (3 ml, 3
mmoles) and then refluxed for 4 hours. It was diluted with chloroform (100 ml),
washed with a saturated aqueous ammonium chloride solution and water and
then the solution was dried over sodium sulfate. The filtrate was evaporated
and the residue was purified by silica gel column chromatography while using
chloroform as the eluent. The product fraction was evaporated to give 50 mg
(yield: 26%) of a yellow powder with a melting point range of 1 97-1 98 °C.
20
25
37
Example 4 - preparation of Q 4 -methvl-biop terin f2-amino-4-methoxv-6-(1 ,2-
dihvdroxvpropvn pteridine)
To a solution of N 2 , 1', 2'-0-triacetyl-biopterin (1,0 g, 2.75 mmoles),
triphenyl-phosphane (12,08 g, 4.13 mmoles) and methanol (0.15 ml, 3.7
mmoles) in dry dioxane (30 ml) was added diisopropyl azodicarboxylate (0.81
g, 4.1 mmoles). After stirring for 1.5 hour at room temperature, the mixture
was evaporated to dryness. The residue was purified by silica gel column
chromatography while using an ethylacetate/CHCI 3 (1:4) mixture as the
eluent. The product fraction was evaporated and dried in vacuum to give 0.4 g
(yield: 38%) of N 2 ,1',2 , -0-triacetyl-0 4 -methylbiopterin. Deacetylatton of this
reaction product (0.28 g, 074 mmole) was done by stirring it in absolute
methanol (20 ml) and triethylamine (4 ml) for 24 hours. Evaporation to
dryness, treatment of the residue with ether, filtration and drying gave 0.172 g
(yield: 83%) of 0 4 -methyl-biopterin with a melting point range of 160-161 °C.
Example 5 - preparation of 2^amino-4-hvdroxvlami nty6-phenvlpteridine.
A suspension of 2,5,6-tnamino-4-methoxypyrimidine dihydrochloride (1 g, 4
mmoles) in methanol (40 ml) was heated to boiling and then a solution of
phenylglyoxalmonoxime (1 g, 6.6 mmoles) in methanol (10 ml) was added
dropwise. A clear solution is obtained from which on reflux for 2 hours a
precipitate was separated out. The solid (hydrochloride salt) was filtered off,
suspended in water (30 ml) and then neutralized to pH 8 by concentrated
ammonia. The resulting precipitate was collected, washed with water and
ethanol and dried at 100 °C to give 0.84 g of a yellow powder (yield: 82%).
Examples 6 to 53 - synthesis of 2-fl mino4-dialkvlamino-6-arvlPteridines. 2-
amino-4-difarvlalkvhamino-6-arvlpteridine s 2-amin(M-alkvlamino-6-arylpten-
dines. 2-amino-4-(N-containina heter ocyclic aminol-6-arvlPteridines and 2-
amino-4^lkoxv-6-arvlpteridines
The procedure for the synthesis of the following 2-amino-4-dialkylamino-6-
arylpteridines, 2-amino-4-dialkylamino-6-arylpteridines, 2-amino-4-alkylamino-
6-arylpteridines, 2-amino-4-(N-containing heterocyclic amino)-6-arylpteridines
and 2-amino-4-alkoxy-6-arylpteridines proceeds in three steps:
38
) a solution of 2 l 6^iamino-4^loro^i>K^lorophenylazopyrimidine (a
compound known from British Patent No. 677,342) (5.0 g, 16.6 mmoles) in
DMF (50ml) and 0.12 mole of the appropriate reactant, being selected from
the group consisting of secondary alkylamines and arylalkylamines (e.g.
dimethyl-amme in ethanol (50%), diethylamine, di-n-propylamine or
dibenzylamine), primary amines (e.g. an adamantanamine), heterocyclic
amines (e.g. morpholine, piperidine, pyrrolidine, piperazine or N-methyl-
piperazine) and alcaline metal alkoxides (e.g. sodium ethoxide or sodium
isopropoxide), were heated in an oil bath at 70°C for 5 hours. Then water
(50 ml) was added, cooled and the yellow precipitate collected, washed
with water and dried. Recrystallization from ethanol or a DMF/water
mixture provided the relevant 2,6-diamino4-dialkylamino-5-p-chloro-
phenylazopyrimidine, 2 f 6^iamino4-di(arylalkyl)amino-5-p-chlorophenyl-
azopyrimidine, 2 f 6^iamino^^lkyl-amino-5-p-chlorophenylazopyrimidine,
2,6-diamino-4-(N-containing hetero-cyclic amino)-5-p-chlorophenylazo-
pyrimidine or 2,6^iamino-4-alkoxy-5-p-chlorophenylazopyrimidine with a
yield ranging from 55 to 90%
a suspension of the pyrimidine compound (3.28 g, 10 mmoles) resulting
from step (a) in methanol (70 ml) and concentrated ammonia (10 ml) was
reduced in a shaking apparatus under a hydrogen atmosphere in the
presence of a Raney nickel catalyst (3.5 g) for 2 days. The catalyst was
filtered off under argon atmosphere and then the filtrate evaporated in
vacuo to dryness. The residue was treated with ether to remove p-
chloroanilme, filtered and then the solid stirred in methanolic HCI (10%, 50
ml) overnight. The dihydrochloride salt (obtained with a yield ranging from
85 to 90%) of the relevant 2,5 l 6-triamino-4-dialkylaminopyrimidine, 2,5,6-
triamino-4-alkoxypyrimidine, 2,5,6-tnamino-4-di(arylalkyl)aminopyrimidine,
2,5,6-triamino-4-alkylaminopyrimidine or 2,5,6-triamino-4-(N-containing
heterocyclic amino) pyrimidine, was collected and dried in a vacuum
desiccator over KOH
to a boiling solution of the 2,5.6-triamino-4-substituted pyrimidine
dihydrochloride salt (5 mmoles) from step (b) in methanol (20 ml) was
added a solution of the relevant arylglyoxalmonoxime (7 5 mmoles) in
39
methanol (10 ml) dropwise and then the mixture was heated under reflux
for 3 hours. After cooling, the suspension or solution was made alkaline by
means of concentrated ammonia up to pH 9 and the resulting precipitate
was filtered off, washed with water and dried. Recrystallization was done
from ethanol and a DMF/water mixture, respectively, such as to provide a
yellow solid with a yield ranging from 50 to 85%.
The following compounds were prepared according to the above general
procedure:
2-amino-4-dimethylamino-6»phenylpteridine (example 6);
2-amino-4-dimethylamino^-(4-tolyl) pteridine (example 7);
2-amino-4-dimethylamino-6-<4-methoxyphenyl)pteridine (example 8);
2-amino-4-diethylamino-6-phenylpteridine (example 9);
2-amino-4-diethylamino-6-(4-chlorophenyl)pteridine (example 10);
2-amino-4-diethylamino^-(4-methoxyphenyl)pteridine (example 11);
2^mino-4<liethylamino^3,4^imethoxyphenyl)pteridine (example 12);
2-amino-4-dibenzylamino-S-phenylpteridine (example 13);
2^mino^ibenzylamino-6-(4-chlorophenyl)pteridine (example 14);
2^mino-4HJibenzylamino^4-methoxyphenyl)pteridine (example 15);
2^mino^ibenzylamino-6-(3,4-dimethoxyphenyl)pteridine (example 16);
2^mincHl-dipropylamino-6-phenylpteridine(example 1 7);
2^mino^ipropylamino-6-(4-chlorophenyl)pteridine (example 18);
2-amirx)^ipropylamino-6-(4-methoxyphenyl)pteridine (example 19);
2^mino-4<lipropylamino^^3 f 4^imethoxyphenyl)pteridine (example 20);
2^mino-4-morpholino^-phenylpteridine (example 21 );
2^mino-4^onpholino-6^4-chlorophenyl)pteridine (example 22),
2-amino-4-morpholino-6-(4-methoxyphenyl)pteridine (example 23);
2-amino«4-morpholmo-6-(3,4-dimethoxyphenyl)pteridine (example 24);
2-amino-4-piperidino-6^)henylpteridine (example 25);
2-amino-4-piperidino^-{4-chlorophenyl)pteridine (example 26);
2-amino-4-pipendino-6-(4-methoxyphenyl)pteridine (example 27);
2-amino-4-pipendino-6-(3,4-dimethoxyphenyl)pteridine (example 28);
2-amino-4-N-methylpiperazino-6-phenylpteridine (example 29);
2-amino-4-N-methylpiperazino-6-(4-chlorophenyl)pteridine (example 30);
40
2-amino^N-methylpiperazino-6- (4-methoxyphenyl) pteridine (example 31);
2-amino-4-methylpiperazino-6- (3, 4-dimethoxyphenyl) pteridine (example 32);
2-amino-4-pyrrolidino-6- (4-methoxyphenyl) pteridine (example 33);
2-amino-4-piperazino-6-phenylpteridine (example 34);
2-amino-4-piperaano-6- (4-chlorophenyl) pteridine (example 35);
2-amino-4-piperazino-6- (4-methoxyphenyl) pteridine (example 36);
2-amino-4-piperazino-6- (3, 4-dimethoxyphenyl) pteridine (example 37);
2^mino-4-dibenzylamino-6-{3 l 4,5-trimethoxyphenyl) ptendine (example 38);
2-amino-4-morpholino-6- (3, 4, 5-trimethoxyphenyl) pteridine (example 39);
2-amino-4-(3-adamantylamino)-6-{3 l 4 l 5-trimethoxyphenyl) pteridine (example
40);
2-amino^-(3-adamantylamino)-6-naphtylpteridine (example 41 );
2-amino-4-(4-adamantylamino)-6-(3 l 4 1 5-trimethoxyphenyl) pteridine (example
42);
2-amino-4-(4-adamantylam»no)-6-naphtylpteridine (example 43);
2^mino-4-morpholino^3,4-fo(^^
(example 44);
2-amino-4-dimethylamino^3,4-fonrnylidene-3,4-dihydroxyphenyl)pteridine
(example 45);
2-amino-4-pyrroltdino-6-(3, 4-dimethoxyphenyl) pteridine (example 46);
2-amino-4-dimethylamino-6-{3, 4-dimethoxyphenyl) ptendine (example 47);
2-amino-4-dimethylamino-6-methylpteridme (example 48);
2-amino-4-ethoxy-6-phenylpteridine (example 49);
2-amino-4-propylamino^-phenylpteridine (example 50);
2-amino-4-propylamino-6-(3 1 4-dimethoxyphenyl) pteridine (example 51 );
2-acetamido4HSopropoxy-6-(3 > 4-dimethoxyphenyl) pteridine (example 52);
and
2~amino-4-ethoxy-6-(3,4-dimethoxyphenyl)pteridine (example 53);
Example 54 - synthesis of 2.6^iamino-4-ethoxv-pyrimidine
To a solution of sodium (1 .05 g) in ethanol (50 ml) was added 4-chloro-
2,6-diaminopyrimidme (6 g t 41 4 mmoles). The resulting solution was heated
in a reactor for 6 hours at 160 °C. The reaction mixture was cooled down and
41
the precipitated sodium chloride was filtered off. The filtrate was concentrated
and precipitated from ethanol (two times), affording the pure title compound as
a white solid (4.53 g, 72% yield). The spectral data are identical to those
described e.g. by W. Pfleiderer et al. in Chem. Ber. (1961 ) 94, 12
Example 55 - synthesis of 2.6-diamino-4-isoDropoxv-ovrimidine
The same procedure as in example 54 was followed using isopropanol
instead of ethanol. The filtrate was pure enough for further reaction without
purification The spectral data are identical to those described e.g. by W.
Pfleiderer etal. in Chem. Ber. (1961) 94, 12.
Example 5 6 - synthesis of 5-nitros6-2.6-diamino-4-ethoxv-ovrimidine
To a solution of the compound of example 54 (6.13 g, 39.8 mmoles) in
20 % aqueous acetic acid (57 ml) was added dropwise a solution of NaN0 2
(3.29 g) in water (13 ml) at 80 °C. A pink precipitate was formed which was
stirred at 80°C for an additional 2 hours. The reaction mixture was cooled
down in the refrigerator overnight and the resulting precipitate was filtered off,
yielding the title compound as a pink powder (4 98 g, yield 68 %). Spectral
data are identical with those described e.g. by W. Pfleiderer et al. in Chem.
Ber (1961) 94, 12.
Example 57 - synthesis of 5-nitroso-2.6-diamino-4-isopropoxv-pvrimidine
The same procedure was followed as in example 56 but starting from
the compound of example 55. The product has identical spectral data to those
described by W. Pfleiderer et al. (cited supra).
Example 58 - synthesis of 2.5.6-triamino-4-ethoxv-pvrimidine
To a suspension of the compound of example 56 (7.12 g, 38.9 mmoles)
in water (150 ml) at 60 °C was added sodium dithionite (46.7 mmol, 8.12 g).
Additional sodium dithionite was added till the pink colour completely
disappeared and a yellow solution was formed. The solution was stirred at 60
°C for another 4 hours. Water was evaporated and the resulting residue was
precipitated from a small amount of water, providing the title compound as a
42
yellow powder (4.02 g, yield 61 %) Spectral data are identical with literature
data (W. Pfleiderer et al cited supra).
Example 59 - synthesis of 2,5.6-triamino^sopropoxvHPvrimidine
5 The procedure of example 58 was followed, however using the
compound of example 57 as the starting material. The spectral data of the
product obtained are identical with the literature data (W. Pfleiderer et al.
cited supra).
Example 60 - synthesis of 2-amino-4-ethoxv-pteridin
10 To a solution of 2 l 5,64riamino4-ethoxy-pyrimidine (10.54 g, 62.37
mmoles) in ethanol (160 ml) was added glyoxal (40 % solution in water, 2.7
ml, 18.6 mmoles). The reaction mixture was refluxed for 4 hours. Some
insoluble material was filtered off. The filtrate was concentrated in vacuo and
the residue purified by flash chromatography (silica, using a CH3OH/CH2CI2
15 mixture (5:95) as the eluent), providing the pure title compound (7.34 g, yield:
62 %) The spectral data of the product are identical with the literature data
(W. Pfleiderer et al. cited supra)
Example 61 - synthesis of 2-amino^sopropoxv-pteridin
20 The procedure of example 60 was repeated, however using
isopropanol as the solvent instead of ethanol. The spectral data of the product
obtained are identical with the literature data (W. Pfleiderer et al. cited supra).
Example 62 - synthesis of 2-amino-4-ethoxvpteridine-N 8 -oxide
25 To a cooled (0 °C) solution of the compound of example 60 (2.47 g,
12.9 mmoles) in trifluoroacetic acid (53 ml) was added dropwise 2.53 ml of a
35 % aqueous H2O2 solution. The reaction mixture was kept at 4 °C for two
days in the refrigerator, whereby another 1.25 ml of the same H2O2 solution
was added after 1 day. The solution was concentrated in vacuo. The residue
30 was suspended in water and neutralized by the addition of a concentrated
ammonia solution. Evaporation of the solvent in vacuo and purification of the
residue by flash chromatography (silica, using a CH3OH/CH2CI2 mixture (6:94)
as the eluent) provided the title compound as a yellow powder (861 mg, yield:
43
32 %). Mass spectrum data are as follows: m/z (%) 230 ([M+Naf , 30), 208
([M+H]*, 100), 180 [(M+H-ethene)*, 10].
Example 63 - synthesis of 2-arnino-4-isooropoxvpteridine-N 6 -oxide
The procedure as described in example 62 was followed, however
using the compound of example 61 as the starting material. Mass spectrum
data are as follows: m/z (%): 222 ([M+Hf, 100), 180 ([M+H-propenef , 60)
Example 64 - synthesis of 2^amino-6-chlon>4-ethoxvDteridine
A suspension of the compound of example 62 (460 mg, 2.22 mmoles)
in acetyl chloride (5.5 ml) was stirred at -40 °C. Trifluoroacetic acid (1.69 ml)
was then added dropwise. The resulting solution was slowly warmed up to 0
°C and stirred for an additional 4 hours at 0 °C. Reaction was carefully
quenched with ice, followed by neutralization with a concentrated ammonia
solution (pH = 8). The aqueous phase was extracted with CH 2 CI 2 (five times).
The combined organic layers were concentrated in vacuo and the residue was
purified by flash chromatography (silica, using a CH 3 OH/CH 2 CI 2 mixture (1:99)
as the eluent), thus providing the title compound as a yellow powder (360 mg,
yield: 72 %). This compound was further characterized as follows:
- mass spectrum: mfc (%): 226 ([M+H]*, 1 00),
- 1 H-NMR (200 MHz, DMSO-d 6 ): 5 1.42 (3 H, t), 4.52 (2 H, q), 7.42 (2 H,
d) and 8.85 (1 H,s)ppm,
- 13 C-NMR (50 MHz, DMSCW 6 ): 5 14.19, 63.58, 121.74, 140.22, 150.99,
156.13, 161.98 and 165.97 ppm.
Example 65 - synthesis of 2-aminch6-chloro-4HSopropoxvpteridine
The procedure as described in example 64 was followed, however
starting from the compound of example 63 The mass spectrum data of the
resulting compound are as follows: m/z (%): 240 ([M+Hf, 55), 198 ([M+H-
propene]*, 100).
44
Examples 66 to 83 - synthesis of 2-amino-6-arvl-4-ethoxvptendines and 2-
amino-6-heteroarvl-4-ethoxvpteridines
The general procedure used for preparing 2-amino-6-aryl-4-ethoxy-
pteridines is as follows, to a degassed solution of the compound of example
5 64 (50 mg, 0.22 mmole) in THF (5 ml) was added a degassed solution of
sodium carbonate (5 ml of a 0.4 M solution in water), tetrakis(triphenyl-
phosphine) palladium (0.013 mmole, 14 mg) and an arylboronic or (examples
72 and 73) heteroarylboronic acid (0.22 mmole). The solution was refluxed for
4 hours Solvents were concentrated in vacuo and the residue was purified by
10 flash chromatography (silica) with an appropriate CH 3 OH/CH 2 CI 2 mixture (2:98
or 3:97) as the eluent (except for the compound of example 82, which was
eluted with an acetone/CH 2 CI 2 (7:3) mixture). This procedure provided, with a
yield ranging from 16 % to 60 % depending upon the aryl or heteroaryl group
(from the arylboronic or heteroarylboronic acid) introduced at the 6-position of
15 the pteridine ring, the following pure final compounds which were
characterized by their mass spectrum MS and optionally by their 'H-NMR (200
MHz, DMSO-cfe) spectrum.
- 2-amino-6-(p-methoxyphenylH-ethoxy-pteridine (example 66): MS 298
([M+Hf, 100), 270 ([M+H-ethenef, 55);
20 - 2^minc>^o^thoxyphenylH-ethoxy-pteridine (example 67): MS 298
([M+Hf, 100), 270 ([M+H-ethenef, 30);
- 2^mino-6-<m-methoxyphenylH-ethoxy-pteridine (example 68): MS
298 <[M+Hf, 100), 270 ([M+H-ethenef, 35); 'H-NMR: 1.46 (3 H, t),
3.85 (3 H. s). 4 58 (2 H, q), 7.06 (1 H, dd). 7.33 (2 H, br s), 7.46 (1 H, t),
25 7.68(1 H,m) and 9 43(1 H,s)ppm;
- 2-amino-6-<3,4-difluorophenyl)-4-ethoxy-pteridine (example 69): MS
304 ([M+Hf ,100), 270 ([M+H-ethenef, 35); 'H-NMR: 1.45 (3 H, t), 4.57
(2 H, q), 7.42 (2 H, br s), 7.60 (1 H, q), 7.98 (1 H, d), 8.16 (1 H, t) and
9.42 (1 H, s) ppm;
30 - 2-amino-6-(p-dimethylaminophenyl)-4-ethoxy-ptendine (example 70):
MS 311 ([M+Hf ,100), 283 ([M+H-ethenef, 35);
- 2-amino-6-(p-trifluoromethylphenyl)-4-ethoxy-pteridine (example 71):
MS 336 ([M+Hf ,100), 308 ([M+H-ethenef, 50);
45
- 2-amino-6^2-thienyl)-4-ethoxy-pteridine (example 72): MS 274 ([M+H]*,
100), 246 ([M+H-ethene]*, 40);
- 2-amino-6-(3-thienyl)-4-ethoxy-ptericline (example 73): MS 274 ([M+H]*,
100), 246 ([M+H-ethener, 45);
- 2^mino-6-(3,4-dichlorophenyl)-4-«thoxy-pteridine (example 74): MS
337 ([M+H]*,1O0); 'H-NMR: 1.46 (3 H, t), 4.59 (2 H, q), 7.42 (2 H, br s),
7.81 (1H, d), 8.14 (1 H, dd), 8.37 (1 H, d) and 9.47 (1 H, s) ppm;
- 2-amino-6-(p-cyanophenyl)-4-ethoxy-pteridine (example 75): MS 293
({M+H]*. 100), 265 ([M+H-ethener, 65);
- 2-amino-6-{p-ethoxyphenyl)-4-ethoxy-pteridine (example 76): MS 312
([M+H]*, 100), 284 ([M+H-ethene] + , 70);
- 2-amino-6-(p-fluorophenyl)-4-ethoxy-pteridine (example 77): MS 286
([M+H]*, 100), 258 ([M+H-ethene)*, 45);
- 2-amino-6^p-ethylphenyl)-4-ethoxy-pteridine (example 78): MS 296
([M+H]*, 100), 268 ([M+H-ethene)*, 45);
- 2-amino-6-(p-acetylphenyl)-4-ethoxy-pteridine (example 79): MS 310
([M+H]*, 1 00), 282 ([M+H-ethene]*. 60);
- 2-amino-6-(3-methyl-4-fluorophenyl)-4-ethoxy-pteridine (example 80):
MS 300 ([M+H]*, 1 00), 272 ([M+H-ethene]*, 30);
- 2-amino-6-(p-thiomethylphenyl)-4-ethoxy-pteridine (example 81): MS
314 ([M+H]*, 100), 286 ([M+H-ethene]*, 35);
- 2-amlno-6-(p-N,N-dimethylbenzamido)-4-ethoxy-pteridine (example 82)
MS 338 ([M+H]*, 100), 311 ([M+H-ethene]*, 15), and
- 2-amino-6-(3,4-dimethoxyphenyl)-4-ethoxy-ptendjne (example 83): MS
328 ([M+H]*, 100), 300 ([M+H-ethene]*, 40).
Examples 84 to 98 - synthesis of 2-amino-6-arvl-4-isopropoxypteridines and 2-
amino-6-heteroan/l-4-isopropoxvpteridines
The procedure as described in examples 66-83 was followed while
using 2-amirK)-6-chloro-4-isopropoxypteridine as the starting material, except
that longer reaction times were needed (refluxing overnight instead of 4
hours). This procedure provided, with a yield ranging from 10 % to 70 %
depending upon the aryl or heteroaryi group introduced at the 6-position of the
46
ptendine ring, the following pure final compounds which were characterized by
their mass spectrum:
- 2^mino^3^ethyl-4-methoxyphenyl)-4-isopropoxypteridine (example
84): MS 326 ([M+HjMOO), 284 ([M+H-propene]*, 30);
- 2^mino^3,4^1imethylphenyl)-4-isopropoxypteridine (example 85):
MS 310 ([M+Hf.lOO), 268 ([M+H-propene]\ 60);
- 2^minc^3^loro-44rifluoromemylphenyl)^soprt^xypteridine
(example 86). MS 384 ([M+H]*, 20), 342 ([M+H-propene]*, 50);
- 2^mino^^3-chloro-4-fluorophenyl)-4-isopropoxypteridine (example
87) : MS 334 ([M+H]*, 20), 292 ([M+H-propene]*, 50);
- 2-amino-6-(p-N,N-diethylbenzamido)-4Hsopropoxypteridine (example
88) : MS 381 ([M+Hf, 100);
- 2^minc^p-trffluoromethylphenyl)-4H'sopropoxypteridine (example
89) : MS 350 ([M+H]*, 1 00), 308 ([M+H-propene]*, 30);
- 2-amino-6-(3,4-difluorophenyl)-4Hsopropoxypteridine (example 90): MS
31 8 ([M+H]*, 100), 276 ([M+H-propene]*, 50);
- 2-amino^-(p-methoxyphenyl)-4-isopropqxypteridine (example 91): MS
312 ([M+H]* ( 100), 270 ([M+H-propene]*, 50);
- 2-amino^-(p-ethoxyphenyl)-4-isopropoxypteridine (example 92). MS
326 ([M+H]*, 55), 284 ([M+H-propener. 1 00);
- 2^mino-6-(p-dimethylben2amido)-4-isopropoxypteridine (example 93):
MS 353 ([M+H]*, 75), 311 ([M+H-propener, 100);
- 2-amino-6-(3-thienyl)-4-isofropoxypteridine (example 94): MS 288
([M+H]*. 55), 246 ([M+H-propene]*. 100);
- 2-amino-6-(p-cyanophenyl)-4-isopropoxypteridine (example 95): MS
307 ([M+H]*, 40), 265 ([M+H-propene]*. 100);
- 2-amino-6-(p-benzoic acid methyl ester)-4-isopropoxypteridine (exam-
ple 96): MS 340 ([M+H]*, 75), 298 ([M+H-propene]*, 100);
- 2-amino-6-(p-acetylphenyt)-4-isopropoxypteridine (example 97) MS
324 ([M+H]*, 55), 282 ([M+H-propene]*, 1 00); and
- 2-amino-6-(3,4-dimethoxyphenyl)-4-isopropoxypteridine (example 98):
MS 342 ([M+Hr. 100), 300 ([M+H-propene]*, 60).
47
Example 99 - synthesis of 2.6-diamino-5^iitroso-4-hvdroxvpvnmidine
To a solution of 2,6-diamino4-hydroxypyrimidine (12.9 g, 102.2
mmoles) in 200 ml of a 10% acetic acid solution in water at 80 °C was added
dropwise a solution of NaN0 2 (7.05 g, 102.2 mmoles) in 20 ml water. A pink
5 preciprtate was formed, which was further stirred for 1 hour at 80 °C. The
reaction mixture was cooled down in the refrigerator overnight. The precipitate
was filtered off and dried over P 2 0 5> providing the title compound as a pink
powder (15.43 g, yield: 97%). The spectral data are in accordance with
literature data (Landauer et al. in J. Chem. Sac. (1953) 3721-3722).
10
Example 100 - synthesis of 2.5.64riamino-4-hydroxypvrimidine
A suspension of the compound of example 99 (15 g, 96.7 mmoles) in
an ammonium sulfide solution (20 % in water, 200 ml) was stirred overnight at
50 °C The reaction mixture was cooled down in the refrigerator and the
15 precipitate was filtered off, providing the title compound as a yellow powder
(11.33 g, yield: 83 %). The spectral data are identical with literature data
(Landauer et al. ated supra).
Example 101 - synthesis of 2-amino-6-(3 t 4<iimethoxyphenyl)pterine
20 To a boiling solution of the compound of example 100 (2.4 g, 17
mmoles) in methanol (100 ml, with 0.9 N HCI) was added dropwise a solution
of 3,4-dimethoxyphenylglyoxal mono-oxime (3.8 g, 18 mmoles) in methanol
(100 ml). The reaction mixture was heated under reflux for 4 hours. The
precipitate formed was filtered off, washed with water, then ethanol and
25 diethyl ether, and dried over P2O5 under vacuum, providing the title compound
as a yellow powder (4.33 g, yield: 85 %). This compound was further
characterized by the following spectra:
- ! H-NMR (500 MHz, TFA): 6 4.11 (3 H, s), 4.07 (3 H, s), 7.21 (1 H, d),
7.78 (1 H, dd), 7.81 (1 H, d) and 9.32 (1 H, s) ppm;
30 - 13 C-NMR (125 MHz, TFA): 6 56.39, 56,7, 111.94, 113.21, 123.22,
127.41, 127.91, 145.92, 149.39, 150.46, 152 47, 153.15, 155.13 and
161.59 ppm.
48
Example 102 - sy nthesis of 2-acetvlamino-6-(3.4-<jimethoxvDhenvnDterine
A suspension of the compound of example 101 (10.46 g, 35 mmoles) in
acetic anhydride (600 ml) and acetic acid (200 ml) was refluxed for 1 hour until
a clear solution was formed By cooling down the reaction mixture in the
5 refrigerator, the precipitate formed was filtered off, washed with ethyl acetate
and diethyl ether, and then dned over P2O5 under vacuum, providing the title
compound as a yellow powder (9.19 g, yield: 77 %). This compound was
further characterized by the following spectra:
- MS: m/z(%): 300 ([M+H]*, 100);
10 - 'H-NMR (200 MHz, DMSO-d 6 ): 5 2.22 (3 H, s), 3.84 (3 H, s). 3.87 (3 H,
s), 7.14 (1 H, d), 7.75 (2 H, m) and 9.51 (1 H, s) ppm.
Example 103 - synthesis of 2^acetvlamin&4-(1.2.4-triazolvt^-6-f3.4-dimethoxv-
phenvQpteridine
15 To a solution of phosphorus oxychloride (1.68 ml, 18 mmoles) and
1,2,4-tnazole (4.96 g, 72 mmoles) in dry pyridine (110 ml) was added the
compound of example 102 (2.45 g, 7.18 mmoles). The suspension was stirred
at room temperature for 4 hours. The precipitate was filtered off, washed with
pyridine, toluene and diethyl ether. The resulting solid was dried over P2O5
20 under vacuum, providing the title compound as a yellow powder (2 g, yield: 80
%) which afforded the following mass spectrum 392 ([M+H]*, 100).
Examples 104 and 105 - synthesis of 2-amino-4-mercaptoethvl-6-(3.4-
dimethoxvphenvltoteridine and 2-aminc-4-mercaptoisopropvl-6-f3.4-
25 dimethoxvphenvn ptendjng
To a suspension of the compound of example 103 (0.25 mmole, 100
mg) in dioxane (5 ml) was added 1 mmole of either ethanethiol (example 104)
or isopropanethiol (example 105) and sodium (12 mg, 0.5 mmole). The
suspension was stirred for 24 hours at room temperature. The solvent was
30 concentrated in vacuo and the residue purified by flash chromatography
(silica, using a CH3OH/CH2CI2 mixture (5:95) as an eluent), followed by
purification by preparative TLC, providing the pure title compounds as yellow
49
powders with yields ranging from 20 to 30%. Both compounds were
characterized by their mass spectrum as follows:
- 2-amino4-mercaptoethyl-€-{3,4-dimethoxyphenyl) pteridine: 344
([M+H]*, 100);
5 - 2^mino-4-rnercaptoisopropyl-6-(3,4-dimethoxyphenyl) pteridine- 357
([M+Hf, 100).
Example 106 - synthesis of a mixture of 2.4<liamino-6-(PHnethoxvphenvl)
pteridine and 2.4^iamino-7^p^ethoxvphenvl)pteridine
10 2 f 4,5,64etra-aminopyrimidine (10 mmoles, 1.4 g) was dissolved in water (50
ml) and the pH was adjusted to 9 with ammonium hydroxide. A solution of 4-
methoxyphenylglyoxal (11 mmoles, 1.8 g) in ethanol (10 ml) was added
dropwise and the solution was refluxed for 1 hour. The yellow precipitate
formed was filtered off and washed with water, ethanol and diethyl ether. NMR
IS analysis reveals the obtention of a mixture (1 2 g, 45 % yield) consisting of 87
% of 2,4-diamino-7-(p-methoxyphenyl)pteridine and 13 % of 2,4-diamino-7-(p-
methoxy-phenyl)pteridine. 1 H-NMR (500 MHz, TFA): 5 4.04 (3 H, s), 4.08 (3 H,
s) t 7.15 (2 H, d) t 7.25 (2 H, d), 8.19 (2 H, d), 8.30 (2 H, d), 9.27 (1 H, s) and
9 37 (1 H, s) ppm
20
Example 107 - synthesis of a mixture of 2^amino6-(p-methoxvphenvl)pterin
and 2-amino-7-(xHnethoxyphenynpterin
The mixture obtained in example 106 (1.2 g, 4.5 mmoles) was
suspended in NaOH 1 N (80 ml) and refluxed till a solution was obtained The
25 hot solution was treated with acetic acid till pH 5, then cooled down and the
resulting precipitate was filtered off and washed with water, ethanol and
diethyl ether, providing a mixture of 2-amino-6-(p-methoxyphenyl)pterin and 2-
amino-7-(p-methoxyphenyl) pterin as a yellow powder (1 g, yield. 82 %). Mass
spectrum: 270 ([M+Hf, 100).
30
Example 108 - synthesis of 2-acetylamino~6-{p-methoxvphenvl)pterin and 2-
acetvlamino-7"fPHnethoxvphenvl)pterin
50
A suspension of the mixture obtained in example 107 (7.43 mmoles, 2
g) was suspended in a mixture of acetic anhydride (50 ml) and acetic acid (50
ml). The suspension was refluxed for 4 hours till a dear solution was obtained.
Some insoluble material was filtered off and the solution was partly
5 evaporated till precipation starts. Further precipitation was achieved overnight
in the refrigerator. The resulting precipitate was filtered off and washed with
ethyl acetate and diethyl ether, providing a mixture of 2-acetylamino-6-(p-
methoxyphenyl)pterin and 2-acetylamino-7-(p-methoxyphenyl)pterin as a
yellow powder (2.1 g, 91 % yield). Mass spectrum: 312 ([M+H]*, 100).
10
Example 109 - synthesis of 2-acetvlamino-4-f1.2.4-triazolvn-6-fp-methoxv-
Phenvh pteridine and 2-acetvlaminc~4-n.2.4-triazolvlWp-methoxvDhenvn
pteridine
To a suspension of the mixture obtained in example 108 (1.5 g, 4
15 mmoles) in dry pyridine (100 ml) was added 1 ,2,4-triazole (830 mg, 12
mmoles) and 4-chlorophenyl phosphorodichloridate (1 ml, 6 mmoles). The
suspension was stirred for 2 days at room temperature under nitrogen. The
solvents were removed in vacuo. The solid matenal was suspended in
dichloromethane and washed with 2 % HCI. Evaporation of the solvents
20 provided a mixture of 2-acetylamirK>4-<1 ,2,4-triazolyl)-6-(p-methoxyphenyl)
pteridine and 2-acetylamino-4-(1,2,4-triazolyl)-7-(p-methoxyphenyl)pteridine.
Example 110 - synthesis of 2-amino-4HSODroooxv-7-fp-methoxvphenvn
pteridine
25 To a suspension of the mixture obtained in example 109 (180 mg, 0.50
mmole) in isopropanol (8 ml) was added sodium (23 mg, 1 mmole). The
suspension was stirred at room temperature overnight. The solvents were
evaporated and the residue was purified by preparative TLC (silica, using a
methanol/CH2CI 2 (7:93) mixture as the eluent). At this stage, both regio-
30 isomers obtained were separated, thus providing the pure title compound as a
yellow powder (yield- 45 %) which was further characterized by its mass
spectrum: 312 ([M+Hf, 65), 270 flM+H-propene]*, 100).
51
Example 111 - synthesis of 2-amino-4HsoproDoxv-7-f3.4-dimethoxvphenvn
pteridine
The sequence of reactions described in examples 106 to 110 was
followed, however starting from 3,4-dimethoxyphenylglyoxal instead of 4-
5 methoxyphenylglyoxal in the first step. This provided 2-amino-4-isopropoxy-7-
(3,4-dimethoxyphenyl) pteridine, a compound which was further characterized
by its mass spectrum: 342 ([M+Hf. 55), 300 ([M+H-propenef, 75).
Example 112 - synthesis of 2-amino^4-ethoxv-7-<3.4-dimethoxvphenvn
10 ptendine
The sequence of reactions described in examples 106 to 110 was
followed, however starting from 3,4-dimethoxyphenylglyoxal instead of 4-
methoxyphenylglyoxal in the first step, and from ethanol instead if isopropanol
in the last step. This provided 2-amino-4-ethoxy-7-(3,4-dimethoxyphenyl)
15 pteridine, a compound which was further characterized as follows"
- MS: 328 ([M+HJ\100), 300 ([M+H-ethenef , 40);
- 'H-NMR (500 MHz, DMSO-cfe): 6 1.44 (3 H, t), 3.86 (3 H, s), 3.88 (3 H,
s), 4.54 (2 H, q), 7.13 (1 H. d), 7.16 (2 H, br s), 7.85 (1 H, d), 7.88 (1 H,
dd) and 9.06 (1 H,s)ppm;
20 - 13 C-NMR (125 MHz. DMSO-d 6 ): 6 14.25, 5567, 55.76, 63.06, 110.39,
111.89, 121.13, 121.25, 128.24, 136.87, 149.28, 151.62, 155.82,
156.72, 162 03 and 166.70 ppm.
Example 113 - synthesis of 2^amino-4-methoxv-7-(3.4-dimethoxvphenvn
25 pteridine
The sequence of reactions described in examples 106 to 110 was
followed, however starting from 3,4-dimethoxyphenylglyoxal instead of 4-
methoxyphenylglyoxal in the first step, and from methanol instead if
isopropanol in the last step. This provided 2-amino-4-ethoxy-7-(3,4-
30 dimethoxyphenyl) pteridine, a compound which was further characterized by
its mass spectrum: 314 ([M+Hr,100), 300 ([M+H-methanef, 20).
EXAMPLE 1 14 - synthesis of 3.4-dimethoxvphenvlglvoxalmonoxime
52
Se0 2 (0.33 mole) was heated to 50°C in a mixture of dioxane (250 ml) and
water (10 ml) After dissolution of Se0 2 , 3,4-dimethoxyacetophenone (0.3
mole) was added and the mixture heated under reflux for 16 hours. The hot
solution was filtered in order to remove selenium, the filtrate was evaporated,
5 the oily residue dissolved in CHCI 3 (300 ml), then washed with saturated
NaHC0 3 solution (100 ml) and water. The organic phase was dned over
Na2S20 4 , filtered and evaporated. The yellow oil was distilled in vacuum, the
resulting 3,4-dimethoxyphenylglyoxal was dissolved in methanol (50 ml) and
water (200 ml), then acetonoxime (0.25 mole) was added and the pH adjusted
10 to 4 by 2 N HCI. The solution was heated to 50°C for 2 hours, then cooled to
0°C and the resulting crystals collected. After washing with cold water and
drying in a vacuum desiccator, 3,4-dimethoxyphenylglyoxalmonoxime was
obtained with a yield of 71 %, optionally recrystallized from CHCI 3 or acetone,
and characterized by 'H-NMR (200 MHz, DMSO-cfe) showing peaks at 3.84 (3
15 H, s), 7.06 (1 H, d), 7.51 (1 H, s), 7.75 (1 H, d), 8.10 (1 H, s) and 12.51 (1 H,
s) ppm.
Example 115 - alternative synthesis of 2-amino4-isoDroooxv-6-/3 4-
dimethoxvphenyDpteridine
20 To a suspension of the compound of example 59 (1.16 g, 6.34 mmole) in
isopropanol (1.25 M HCI, 30 ml) was added the compound of example 114
(6.34 mmole, 1 32 g). The reaction mixture was refluxed for 5 hours, then
cooled down and the pH was adjusted to 9 by the addition of an aqueous
concentrated solution of NH3 The precipitate was filtered off and further
25 purified by flash chromatography over silica gel, using a isopropanol/C^Cb
(1:99 to 3:97) mixture as the eluent, thus providing as a yellow powder 1.34 g
of 2-amino-4-isopropoxy-6-(3,4-dimethoxyphenyl)pteridine, i.e. the compound
of example 98 (yield: 62 %).
30 Example 116 - synt hesis of 2.6-diamino^4-(1.2.3.6-tetrahvdropvridinvlV-
pyrimidine
To a suspension of 6-chtoro-2,4-diaminopyrimidine (6 g, 41 mmole) in toluene
(50 ml) was added 1 ,2,3,6-tetrahydropyridine (8.23 ml, 91 mmole). The
53
resulting suspension was heated to reflux until a solution was obtained, then
the solution was refluxed for 5 hours The reaction mixture was cooled down
and water was added. The precipitate formed was filtered off and washed with
toluene, providing 2,6-diamina4-(1,2 r 3,6-tetrahydropyridinyl)-pyrimidine as a
5 white powder (7.4 g, yield 94 %).
Example 117 - synthesis of 5-nitroso-2.6-diamino4-(1,2.3.6-tetrahvdro-
pyridinvltovrimidine
To a solution of the compound of example 1 16 (7.4 g, 38.7 mmole) in
10 water (80 ml) and acetic acid (3.87 ml) was added a solution of sodium nitrite
(2 94 g, 42.6 mmole) in water. The pink precipitate formed was filtered off and
washed with water, providing 5-nitroso-2,6-diamino-4-(1,2,3,6-tetrahydro-
pyridinyl)pyrimidine (7.83 g) with a yield of 92 %.
15 Example 1 18 - synthesis of 2.5.6-triamino4-f1.2.3.6-tetrahvdroPvridinvn-
pyrimidine
To a suspension of the compound of example 117 (4 g, 18 mmole) in
water (40 ml) was added sodium dithionite (7.9 g, 46 mmole). The suspension
was heated to 90 °C until a solution was obtained. After cooling down, the
20 2,5,6-tnamino-4-(1 ,2,3,6-tetrahydropyridinyl)pyrimidine precipitate formed was
filtered off and used as such for further reaction.
Example 119 - synthesis of 2-amino^4-(1.2.3.6-tetrahvdropvridinvl>-6-f3.4-
dimethoxvphenyl)pteridine
25 To a solution of the reaction product of example 118 (2.22 g, 10.8 mmole) in
methanol (with 1 N HCI, 50 ml) was added the compound of example 114
(2.26 g, 10.8 mmole). The solution was refluxed for 3 hours. The pH of the
reaction was adjusted to 8 by the addition of an aqueous concentrated
ammonia solution. The resulting precipitate was filtered off and further purified
30 by flash chromatography over silica gel, using a CH 3 OH/CH 2 CI 2 mixture (3.97)
as the eluent. This provided a yellow powder (2.56 g, yield 65 %) of 2-amino-
4-(1,2,3,6-tetrahydropyridinyl)-6-(3,4-dimethoxyphenyl)pteridine which was
characterized by the following spectra
54
- 'H-NMR (200 MHz, DMSO-d*) 5 3,84-3.88 (3 H, s), 4.45 (2 H, s), 4.75
(2 H, s), 5.85-5.94 (1 H, m), 7.12 (2 H, d), 7.40 (2 H. s), 7.66 (1 H, s),
7.72 (2 H, d) and 9.39 (1 H, s) ppm;
- MS:365([M+Hf, 100).
5
Example 120 - TNF-g and IL-1 6 assays
Peripheral blood mononuclear cells (herein referred as PBMC), in
response to stimulation by lipopolysaccharide (LPS), a gram-negative
bacterial endotoxin, produce various chemokines, in particular human TNF-a
10 and IL-1 p. The inhibition of the activation of PBMC can be measured by the
level of suppression of the production of TNF-a or IL-1 p by PBMC in
response to stimulation by LPS
Such inhibition measurement was performed as follows: PBMC were
isolated from heparinized peripheral blood (Buffy coat) by density gradient
15 centrifugation. LPS is then added to the PMBC suspension in complete
medium (10 6 cells /ml) at a final concentration of 1 vgfml The pteridine
derivative to be tested was added at different dilution levels, and the cells
were incubated at 37°C for 72 hours. The supematants were collected, and
TNF-a or IL-ip concentrations were measured with respectively an anti-TNF
20 antibody or an anti-IL-1 p antibody in a sandwich ELISA (Duo Set ELISA
human TNFa, commercially available from R&D Systems, United Kingdom).
The colorimetric reading of the ELISA was measured by a Multiskan RC plate
reader (commercially available from ThermoLabsystems, Finland) at 450 nm
(reference wavelength 690 nm). Data analysis was performed with Ascent
25 software 2.6. (also from ThermoLabsystems, Finland): a standard curve
(recombinant human TNFa) was drawn and the amount (pg/ml) of each
sample on the standard curve was determined.
The % inhibition of human TNF-a production or human IL-1p was
calculated using the formula :
30 % inhibition = (pg/ml in sample - pg/ml min.) / (pg/ml max. - pg/ml min.) -1
wherein: - min * pg/ml in culture medium without test compound, and
- max.: pg/ml in culture medium + LPS without test compound.
55
Tables 1 and 2 hereinafter show the IC50 values (expressed in uM) of the
tested compounds, being represented by the general formula (I), in these
TNF-a and IL-1 assays.
TABLE 1
Example n°
TNF-a
IL-1
24
0.4
5.5
85
6.7
>40
98
3.5
>40
119
0.5
15
5
TABLE 2
Example n°
TNF-a
Example n°
TNF-a
59
8.0
83
6.6
63
4.0
85
6.7
65
9.1
87
7.5
66
4.5
89
9.1
67
10.0
90
6.6
68
10.0
91
6.2
72
8.5
92
10.0
77
8.1
94
7.6
78
8.5
95
6.3
80
68
97
9.1
81
10.0
98
35
Example 121 - protection against lethal toxic shock.
When a control group of 14 sham treated (saline injection) C3H mice
10 are injected intraperitoneously with 100 pg LPS per mouse, all animals die
within 1-3 days after injection. However when a group (16 animals) of the
same C3H mice were treated for 2 days with the ptendine derivative of
example 24 (intraperitoneous administration of 20 mg/kg/day; a first injection
at the same time as the LPS injection, a second injection 24 hours later), all
15 mice were significantly protected from acute shock related mortality:
56
- 14 animals permanently survived the challenge of a LPS lethal dose,
and
- 2 animals showed a significantly prolonged survival (5 days).
Thus it can be concluded that treatment with a pteridine derivative of the
5 invention provides an unexpectedly nearly complete protection against lethal
toxic shock.
Example 122 - prote ction aoainst a lethal dose of TNF-q
A model of TNF-a induced shock in C57BL/6 male mice was performed as
1 0 follows. Animals from the control group received an intravenous administration
of a lethal dose of TNF-a (10 ug) in the tail. Animals from the test group
received three intraperitoneous injections of a pteridine derivative (20
mg/kg/day) respectively 48 hours, 24 hours and immediately before an
intravenous injection of TNF-a (10 ug).
15 Body temperature, a clinical sign of TNF-induced shock, was followed for
48 hours in control mice and in mice receiving the pteridine derivative of
example 24: the body temperature of control mice dropped significantly
(28.2X) when compared to mice receiving the test compound (30.1°C).
The survival rate (at least 50%) of mice that received the pteridine
20 derivatives of the invention in addition to the TNF-a dose (10 ug) was quite
substantial, as shown in table 3.
TABLE 3
Example n°
Total number of
animals
Animals surviving 48 hours
after TNF-a administration
control
9
0
24
9
7
98
6
3
119
6
3
57
This model therefore demonstrates that in vivo treatment with a
pteridine derivative of this invention provides substantial and significant
protection against a lethal dose of TNF-a.
5 Example 123 - reduction o f tumor growth while inhibiting TNF-a toxicity
A tumor model of melanoma (B16BL76) in C57BL6 (B6) mice was
performed as follows. On day 1 , a group of 18 B6 mice were injected with 1 .5
x 10 6 B16BU6 melanosarcoma cells. The group was further divided into the
following sub-groups 3 days after the tumor cells injection:
10 - a first control sub-group of 6 mice received vehicle (physiological
solution) 3 times a week starting on day 3;
- a second control sub-group of 5 mice received TNF-a (15 ug) on day 5
and, for surviving animals, TNF-a was again administered 3 times a
week for 2 weeks;
15 - a test sub-group of 7 mice intraperitoneously received the pteridine
denvative of example 24 at a dose of 20 mg/kg on each of days 3, 4
and 5; the latter third injection on day 5 occurred 2 hours before a first
TNF-a intravenous injection (15 ug). Then the test compound (20
mg/kg/day) and TNFa (15 UQ/day) were administered each
20 subcutaneously3timesaweekfor2weeks.
Substantial protection against TNF-a toxicity was achieved by the pteridine
derivative of the invention in tumor bearing mice: 5 out of 7 animals of the test
sub-group survived, compared to none of the second control group (which all
died during day 5).
25 Furthermore, histological studies after two weeks treatment show that
administration of the pteridine derivative of example 24 together with TNF-a
leads to a significant reduction of tumor growth: the average tumor size (tumor
size was measured as the largest diameter multiplied by the smallest
diameter) in the test sub-group was 144 mm 2 , whereas the average tumor size
30 in the first control group was 439 mm 2 These data clearly demonstrate that
the pteridine derivative of example 24 effectively protects mice against the
toxicity of TNF-a while preserving its anti-tumor effects.
58
CLAIMS
1. Use of a pteridine derivative for the manufacture of a medicament for the
prevention or treatment of a disorder in a mammal, the said disorder being
selected from the group consisting of:
- septic or endotoxic shock,
- TNF-a- mediated diseases,
- pathologies and conditions associated with and/or induced by abnormal
levels of TNF-a occurring in a systemic, localized or particular tissue type or
location in the body of the mammal,
- toxic effects of TNF-a and/or anti-cancer chemotherapeutic agents,
- injuries after irradiation of a tissue of the mammal by radio-elements, and
- cachexia,
the said pteridine derivative having the general formula (I):
wherein X represents an oxygen atom or a group with the formula S(0) m wherein m
is an integer from 0 to 2, or a group with the formula NZ and wherein:
- Ri is a group selected from the group consisting of C1-7 alkyl, C2.7 alkenyl,
C2-7 alkynyl, C3-10 cycloalkyl, C3.10 cycloalkenyl, aryl, alkylaryl, arylalkyl,
heterocyclic, heterocyclic-substituted alkyl and alkyl-substituted
heterocyclic, each of said groups being optionally substituted with one or
more substituents selected from the group consisting of halogen, Ci^
alkyl, C1.4 alkoxy, C 2 . 7 alkenyl, C2-7 alkynyl, halo C1.4 alkyl. C3.10
cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted
alkyloxy, thio C,. 7 alkyl, thio C3-10 cycloalkyl, thioaryl, thioheterocyclic,
arylalkylthio, heterocyclic-substituted alkylthio, formyl, hydroxyl, suKhydryl,
nitro, hydroxylamino, mercaptoamino, cyano, carboxylic acid or esters or
thioesters or amides or thioamides or halides or anhydrides thereof,
thiocarboxylic acid or esters or thioesters or amides or thioamides or
58
59
halides or anhydrides thereof, carbamoyl, thiocarbamoyl, ureido, thio-
ureido, amino, cycloalkylamino, alkenylamino, cycloalkenylamino,
alkynylamino, arylamino, arylalkyl-amino, hydroxylalkylamino,
mercaptoalkyl-amino, heterocyclic amino, hydrazino, alkylhydrazino and
phenyl-bydrazino; or R 1 is a carboxyalkyl, carboxyaryl, thiocarboxyaryl or
thiocarboxyalkyl group;
Z is a group independently defined as Ri or Z is hydrogen or the group NZ
together with Ri is either hydroxylamino or an optionally substituted
heterocyclic group containing at least one nitrogen atom;
R2 is selected from the group consisting of amino; acylamino;
thioacylamino, carbamoyl; thiocarbamoyl, ureido; thioureido, sulfon-amido;
hydroxylamino; alkoxyamino; thioalkylamino; mercaptoamino, hydrazino;
alkylhydrazino; phenylhydrazino; optionally substituted heterocyclic
radicals, C1-7 alkylamino, arylamino; arylalkylamino; cycloalkylamino;
alkenylamino; cycloalkenylamino; heterocyclic amino; hydroxyalkylamino;
mercaptoalkylamino; C1-7 alkoxy; C3.10 cycloalkoxy; thio C1.7 alkyl;
arylsulfoxide; arylsulfone; heterocyclic sulfoxide; heterocyclic sulfone; thio
C3-10 cycloalkyl; aryloxy; arylthio; arylalkyloxy; arylalkylthio; oxyheterocyclic
and thioheterocyclic radicals,
R4 is an atom or a group selected from the group consisting of hydrogen;
halogen, C1-7 alkyl; C2-7 alkenyl; C2-7 alkynyl; halo C1.7 alkyl; carboxy C1-7
alkyl; acetoxy C1-7 alkyl; carboxyaryl; C1-7 alkoxy; C3-10 cycloalkoxy;
aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic-substituted alkyloxy,
thio C1-7 alkyl, thio C3.10 cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio;
heterocyclic-substituted alkylthio; amino; hydroxylamino; mercapto-amino;
acylamino, thioacylamino, alkoxyamino; thioalkylamino; acetal; thioacetal;
carboxylic acid; carboxylic acid esters, thioesters, halides, anhydrides,
amides and thioamides, thiocarboxylic acid; thiocarboxylic acid esters,
thioesters, halides, anhydrides, amides and thioamides; hydroxyl,
sulfhydryl; nitro; cyano; carbamoyl; thiocarbamoyl, ureido; thio-ureido;
alkylamino; cycloalkylamino; alkenylamino; cycloalkenylamino; alkynyl-
59
60
amino; arylamino; arylalkylamino; hydroxyalkylamino; mercapto-
alkylamino; heterocyclic amino; heterocyclic-substituted alkylamino,
oximino; alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino;
cysteinyl add, esters, thioesters, halides, anhydrides, amides and
thioamides thereof; aryl groups optionally substituted with one or more
substituents selected from the group consisting of halogen, C1.7 alkyl, C1-7
alkoxy, C2-7 alkenyl, C 2 -? alkynyl, halo C1.7 alkyl, nitro, hydroxyl, sulfhydryl,
amino, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyhetero-cyclic,
heterocyclic-substituted alkyloxy, thio C1-7 alkyl, thio C^o cycloalkyl.
thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio,
formyl, carbamoyl, thiocarbamoyl, ureido, thio-ureido, sulfonamido,
hydroxylamino, alkoxyamino, mercaptoamino, thioalkylamino, acylamino,
thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or
anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or
halides or anhydrides or amides thereof, alkylamino, cycloalkylamino,
alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkylamino,
hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino,
alkyl-hydrazino and phenylhydrazino; optionally substituted heterocyclic
radicals; aromatic or heterocyclic substituents substituted with an aliphatic
spacer between the pteridine ring and the aromatic or heterocyclic
substituent, whereby said aliphatic spacer is a branched or straight,
saturated or unsaturated aliphatic chain of 1 to 4 carbon atoms which may
contain one or more functions, atoms or radicals selected from the group
consisting of carbonyl (oxo), thiocarbonyl, alcohol (hydroxyl), thiol, ether,
thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, amino-
acid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido,
thio-ureido, carboxylic aad or ester or thioester or halide or anhydride or
amide, thiocarboxylic acid or ester or thioester or halide or anhydride or
amide, nitro, thio Ct-7 alkyl, thio C3.10 cycloalkyl, hydroxylamino,
mercaptoamino, alkylamino, cycloalkylamino, alkenylamino, cycloalkenyl-
amino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino,
60
61
mercaptoalkylamino, heterocyclic amino, hydrazino, alkythydrazino,
phenylhydrazino, sulfonyl, sulfinyl, sulfbnamido and halogen; branched or
straight, saturated or unsaturated aliphatic chains of 1 to 7 carbon atoms
optionally containing one or more functions selected from the group
consisting of carbonyl (oxo), thiocarbonyl, alcohol (hydroxyl), thiol, ether,
thio-ether, acetal, thio-acetal. amino, imino, oximino, alkykoximino, amino-
acid, cyano, acylamino; thioacylamino, carbamoyl, thiocarbamoyl, ureido,
thio-ureido, carboxylic acid ester or halide or anhydride or amide,
thiocarboxylic acid or ester or thioester or halide or anhydride or amide,
nitro, thio Ci- 7 alkyl, thio C3-10 cycloalkyl, hydroxylamino, mercapto-amino,
alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynyl-
amino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino,
heterocyclic amino, hydrazine alkylhydrazino, phenylhydrazino, sulfonyl,
sulfinyl, sulfonamido and halogen; and
- R3 is an atom or a group defined as FU or R 3 together with R4 forms a
homocyclic or heterocyclic radical;
and/or a pharmaceutical^ acceptable addition salt thereof and/or a
stereoisomer thereof and/or a mono- or a di-/V-oxide thereof and/or a solvate
and/or a dihydro- or tetrahydropteridme derivative thereof.
2. Use according to claim 1, wherein Ri is selected from the group consisting of
methyl, ethyl, isopropyl and pentyl
3. Use according to claim 1, wherein R 3 is 3-thienyl, 2-thienyl or a phenyl group
with one or more substituents.
4. Use according to claim 1, wherein R3 is a phenyl group with one or more
substituents each independently selected from the group consisting of fluoro,
methoxy, ethoxy, trifluoromethyl, dimethylamino, chloro, cyano, methyl, ethyl,
carboxymethyl, methylthio, dimethylcarboxamido, diethylcarboxamido and
methylcarboxylate.
61
62
Use according to claim 1 , wherein:
- XisNZ,
- Z is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl
and benzyl, and
- Ri is selected from the group consisting of methyl, ethyl, n-propyl and
benzyl.
Use according to claim 1 , wherein X is NZ and wherein the group NZ together
with Ri is selected from the group consisting of tetrahydropyridinyl,
hydroxylamino, morpholinyl, piperidinyl, piperazinyl, 1,2,4-triazolyl and N-
methylpiperazinyl.
Use according to claim 1, wherein the pteridine derivative is a compound
selected from the group consisting of.
- 2-amino-4-ethoxypteridine
- 2-amino-4-ethoxy-6-chlcro-pteridine
- 2-amino-4-ethoxy-€-(4-methoxyphenyl)-pteridine
- 2-amino-4-ethoxy-6-(2-methoxyphenyl)-pteridine
- 2-amino-4-ethoxy-6-<3-methoxyphenyl)-pteridine
- 2-amino-4-ethoxy-€-{3,4-difluorophenyl)-pteridine
- 2-amino-4-ethoxy-6-(4-dimethylaminophenyl)-pteridine
- 2-amino-4-ethoxy-6-(4-trifluoromethylphenyl)-pteridine
- 2-amino4-ethoxy-6-(2-thienyl)-pteridine
- 2-amino-4-ethoxy-6-(3-thienyl)-pteridine
- 2-amino-4-ethoxy-6-{3,4-dichlorophenyl)-pteridine
2-amino-4-ethoxy-6-<4-cyanophenyl)-pteridine
2-amino-4-ethoxy-6-(4-ethoxyphenyl)-pteridine
2-amino-4-ethoxy-6-(4-fluorophenyl)-pteridine
2-amino-4-ethoxy-6-(4-ethylphenyl)-pteridine
2-amino-4-ethoxy-6-(4-acetylphenyl)-pteridine
2-aminc-4^oxy^3^uoro-4-methylphenyl)-pteridine
62
63
2-amino-4-ethoxy-6-{4-methylthiophenyl)-pteridine
2-amino-4-ethoxy-6-(4-N,N-dimethylbenzamido)-pter1dine
2-amino-4-isopropoxypteridine
2-amino4-isopropoxy-e<*)loropteridine
2^mino4HSopropoxy^3HTiethyl-4-methoxyphenyl)-pteridine
2-amino^sopropoxy^3,4-dmethylphenyl)-pteridine
2^ino^sopropoxy^3^lor(M-trrfluoromethylphenyl)-pteridine
2-amino^sopropoxy-6-<3-chlorol-4-fluorophenyl)-pteridine
2^mino^sopropoxy^4-N,N-diethylbenzamido)-pteridine
2-amino-^sopropoxy-6-(4-trifIuoromethylphenylH)teridine
2-amino-4-isopropoxy-6-(3,4-difluorophenyl)-pteridine
2-amino-4Hsopropoxy-6-(4-methoxyphenyl)-ptendine
2-ammo-4-isopropoxy-6-(4-ethoxyphenyl)-pteridine
2-amino^sopropoxy^4-N,N^imethylbenzamjdo)-pteridine
2-amino-4-isopropoxy-6-{3-thienyl)-ptendine
2^mino-4-isopropoxy-6-(4-cyanophenyl)-pteridine
2-amino-4-isopropoxy-6-(4-benzoic add methyl ester)-pteridine
2-amino-4-isopropoxy-6-(4-acetylphenyl)-pteridine
2^mino^HSopropoxy^3,4^imethoxyphenyl)-pteridine
2^mino^thylthio^3,4^imethoxyphenyl)-pteridine
2^mincM^sopropylthio-6-<3,4-dimethoxyphenyl)-pteridine
2^mincMHDentoxy-6-styiylpterjdine,
2^min<M-n-pentoxy^1,2<libromo-2^
2^mino-4-melhoxy-6-styryl-7-methoxypteridine,
2,4-diamino^-phenyl-7-methylpteridine,
2-amino-4-dimethylamino-6-phenylpteridine,
2^mino-4-dimethylarnino-6-{4-tolyl)pteridine 1
2-amino-4-dimethylamino-6-(4-methoxyphenyl)pteridine,
2-amino-4-diethylamino-6-phenylpteridine,
2-amincH4-diethylamino^-(4-chlorophenyl)pteridine 1
2^mino-4^1iethylamino-€-{4-methoxyphenyl)pteridine,
64
2^mino^iethylamino^3,4<limethoxyphenyl)pteridine l
2-amino-4-dibenzylamino-6i3henyl pteridine,
2-amino-4^ibenzylamino-^4-chlorophenyl)pteridine l
2^mino-4^ibenzylamino^4HTiethoxyphenyl)pteridine
2^mino-4^ibenzylaminch6^3,4^
2^mino-4-dipropylamino-6-phenylpteridine,
2^mino-4^ipropylamino^4^lorophenyl)pteridine,
2-amino-4^ipropylamino^4^ethoxyphenyl)pteridine,
2^mino-4^ipropylamino^3 t 4^imethoxyphenyl)pteridine,
2^mincHl^oipholino-6-phenylpteridine >
2^mino-4^oipholino^^4-chlorophenyl)pteridine t
2^mino-4^orpholino^4-methoxyphenyl)pteridine,
2^mino-4^rpholino^3,4^imemo
2-amino-4^iperidino-6-phenylpteridine,
2-amino-4^iperidirK)^4-chlorophenyl) pteridine,
2-amino-4^iperidino^4-methoxyphenyl)pteridine,
2^mino^^iperidino^3,4Kiimethoxyphenyl)pteridine l
2-amino-4-N-methylpiperazino-€-phenylptendine,
2^mino^N^ethylpiperazino^4^l^^
2-amino^N-methylpiperazino^
2^mino-4^ethylpiperazino^3,4<limetnoxyphen
2-amirK>-4^yrrolidino^4HTiethoxyphenyl)pterid
2^mincM-piperazinc>-6-phenyl^eridine l
2-amirw>-4^iperazirK>^4Kiilorophen^
2^mino-4i3ip€razirK>^4^ethoxyphenyl)pteridi
2^mino-4^iperazirK>^3 l 4Klimethoxyphenyl)pteridine i
2-amino^ibenzylamino^3,4 t 5-^
2^mincMHrnorpholino^(3 l 4 f 5-trimethoxyphenyl)pteridine (
2-amino^3-adamantylamino)^3 t 4 l 5-trimethoxyphenyO
2-amino^3^amantylamino)-6-naphtylpteridine t
2^mino^4^amantylamino)^3 l 4,5-trimethoxyphenyl)pterkjine i
65
- 2-amino-4-(4-adamantylamino)-6-naphtylpteridine >
- 2^mino^^orpholino^3,4^ormylidene-3,4^ihydroxyphenyl)pteridine,
- 2^mino^imethylamino^^3Aformylidene-3,4-dihydroxyphenyl)
pteridine,
- 2^mino-4-pyrrolidino-6-(3 1 4,dimethoxyphenyl)pteridine >
- 2^mirx>^imethylamino-6-(3,4-dimethoxyphenyl)pteridine,
- 2-amino-4-dimethylamino-6-methylptendine,
- 2-amino-4-ethoxy-6-phenylpteridine,
- 2^mino-4-propylamino^-phenylpteridine 1
- 2^m«no-4^opylamino-6-{3,4<limethoxyphenyl)pteridine,
- 2-acetamido-4-hydraxy-6-(3 1 4-dimethoxyphenyl)pteridine,
- 2-acetamido-4Hsopropoxy-6-(3,4-dimethoxyphenyl)pteridine 1
- 2-amino-4-ethoxy-6-(3,4-dimethoxyphenyl)pteridine 1 and
- 2-amino-4-<1 ,2,3,6-tetrahydropyridinyl)-6-(3,4-dimethoxyphenyl)pteridine.
8. Use according to claim 1, wherein the said disorder is septick shock and the
medicament is for the treatment of a mammal with a serum level of
interleukin-6 above 1 ,000 pg/ml at start of treatment.
9. Use according to claim 1, wherein the said TNF-a-mediated disease is
selected from the group consisting of neurodegenerative diseases,
myelodysplastic syndromes and alcohol-induced hepatitis.
10. Use according to claim 1, wherein the abnormal levels of TNF-a are levels
exceeding by at least 10 % and at most 500% the TNF-a level present in a
normal healthy subject.
65
o
INVESTOR IN PEOPLE
Darren Handley
13 January 2004
Patents Act 1977 : Search Report under Section 17
Documents considered to be relevant:
Category
Relevant
to claims
Identity of document and passage or figure of particular relevance
X
1-3, 5-10
DE 19944767 A
(VASOPHARM) - see page 1, lines 17-50; page
7, lines 15-25; and page 9, line 28-page 11, line
60
X
MO
JP 2003238409 A
(SHIMICK) - see WPI abstract AN-2003-
820621 [77]
X
1,8-10
JP 6192100 A
(ASHAHI) - see WPI abstract AN-1994-260430
[32] and PAJ and paragraphs [0005]-[0007]
X
1.8-10
US 5902810 A
(PFLEIDERER) - see claims 1, 8-9; column 7,
line 6-column 8, line 60
A
WO 00/39129 A
(LEUVEN) - see claims 1 & 6
Categories:
X
Document indicating lack of novelty or inventive step
A
Document indicating technological background and/or state of the art
Y
Document indicating lack of inventive step if combined
with one or more other documents of same category.
P
Document published on or after the declared priority date but before the
filing date of this invention.
&
Member of the same patent family
E
Patent document published on or after, but with priority date earlier
than, the filing date of this application
Field of Search:
Search of GB, EP, WO & US patent documents classified in the following areas of fee UKC*:
Worldwide search of patent documents classified in the following areas of the IPC 7 :
A61K; A61P
The following online and other databases have been used in the preparation of this search report:
WPI, EPODOC, JAPIO, CAS-ONLINE
Application No:
Claims searched:
Hit- *d
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GB 0321384.0
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